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PKM2

Pyruvate kinase M2 (PKM2) is a key enzyme in glycolysis that catalyzes the irreversible conversion of phosphoenolpyruvate (PEP) to pyruvate, thereby generating adenosine triphosphate (ATP) in the final step of the glycolytic pathway.^[1] Encoded by the PKM gene on human chromosome 15 through alternative splicing, PKM2 is one of four mammalian pyruvate kinase isoforms (alongside PKL, PKR, and PKM1) and is characterized by its ability to exist in equilibrium between a high-activity tetrameric form and a low-activity dimeric form, regulated by allosteric effectors such as fructose-1,6-bisphosphate (FBP) and inhibitors like ATP or tyrosine phosphorylation.^[1] This isoform is predominantly expressed in embryonic tissues, proliferating cells, and most tumor cells, where it plays a central role in metabolic reprogramming to support rapid cell division and biosynthetic demands.^[2] In cancer metabolism, PKM2 is upregulated and promotes the Warburg effect, in which cells preferentially perform aerobic glycolysis even in the presence of oxygen, diverting glycolytic intermediates toward pathways like the pentose phosphate pathway and serine biosynthesis to fuel nucleotide synthesis, redox balance, and tumor growth.^[3] Its dimeric form, with reduced enzymatic activity, allows accumulation of upstream glycolytic metabolites that serve as building blocks for proliferation, while the tetrameric form can be induced under specific conditions to meet energy needs.^[1] Elevated PKM2 expression correlates with poor prognosis in various malignancies, including lung, breast, and colorectal cancers, and it has been explored as a diagnostic biomarker, such as in serum or saliva levels for early detection.^[3] Beyond its metabolic functions, PKM2 exhibits non-glycolytic roles, translocating to the nucleus to act as a protein kinase and transcriptional coactivator, phosphorylating substrates like histone H3 and interacting with transcription factors such as HIF-1α and STAT3 to regulate genes involved in angiogenesis, cell cycle progression, and inflammation.^[2] These moonlighting activities contribute to oncogenesis by enhancing survival signals and immune evasion, positioning PKM2 as a multifaceted regulator in both normal development and pathological states like tumorigenesis.^[1] Ongoing research highlights its potential as a therapeutic target, with inhibitors and activators being investigated to disrupt cancer metabolism or restore normal glycolytic flux.^[3]

Molecular Biology

Gene and Alternative Splicing

The PKM gene, which encodes the M1 and M2 isoforms of pyruvate kinase, is located on the long arm of human chromosome 15 at cytogenetic band 15q23.^[4] It spans approximately 32 kb of genomic DNA and consists of 12 exons and 11 introns.^[5] The gene was cloned and characterized in the late 1980s, with overlapping genomic clones covering the entire coding sequence isolated and sequenced by 1988.^[6] Alternative splicing of PKM pre-mRNA produces the tissue-specific isoforms PKM1 and PKM2 through the mutually exclusive inclusion of exon 9 or exon 10, respectively. This process is regulated by heterogeneous nuclear ribonucleoproteins (hnRNPs), including PTB (also known as hnRNP I), hnRNP A1, and hnRNP A2, which bind to splice sites flanking exon 9 to promote its skipping and favor exon 10 inclusion, thereby generating PKM2 transcripts.^[7] These splicing factors are often upregulated by oncogenes like c-Myc, linking the mechanism to cancer progression in studies from the 2000s. The alternative splicing patterns of the PKM gene, including the mutually exclusive exon usage, are evolutionarily conserved across mammals, as evidenced by similar exon structures and isoform production in human, mouse, and rat genomes.^[8] PKM2 mRNA expression is upregulated in embryonic tissues, where it supports proliferative demands, and in tumor cells, where hypoxia-inducible factor 1α (HIF-1α) binds to the PKM2 promoter to enhance transcription under hypoxic conditions.^[9]^[10]

Protein Structure and Isoforms

Pyruvate kinase M2 (PKM2) is a 531-amino acid polypeptide with a calculated molecular weight of approximately 58 kDa. It shares the same genomic origin as PKM1 but differs by 23 amino acids, primarily in the C-terminal region, due to alternative splicing that replaces exon 9 with exon 10. This sequence variation endows PKM2 with unique regulatory properties absent in PKM1. The tertiary structure of the PKM2 monomer comprises four distinct domains: an N-terminal domain (residues 1–43), A domain (residues 44–287), B domain (residues 288–389), and C domain (residues 390–531). The A domain features a large α/β fold typical of nucleotide-binding proteins, while the smaller B domain consists mainly of β-strands. The C domain, also α/β, contributes to inter-subunit contacts. The catalytic active site resides in a cleft formed between the A and B domains, where phosphoenolpyruvate (PEP) and ADP bind. Crystal structures, such as that of the human PKM2 tetramer bound to fructose-1,6-bisphosphate (FBP) and inhibitors (PDB ID: 1T5A), illustrate this architecture and highlight the flexibility of the B domain, which closes over the active site upon substrate binding. In its quaternary structure, PKM2 predominantly assembles as a homotetramer, the form associated with high catalytic activity, though it can dissociate into low-activity dimers or monomers under certain conditions. Dimerization occurs via interfaces on the A domains, while tetramerization is mediated by symmetric contacts between C domains of adjacent dimers. The allosteric activator FBP binds at the C-C interface, promoting a conformational shift from a tense (T-state) tetramer to a more open relaxed (R-state) form that enhances substrate affinity. This oligomeric plasticity distinguishes PKM2 from other isoforms and enables fine-tuned metabolic control. Compared to PKM2, the PKM1 isoform—predominant in post-mitotic tissues such as muscle and brain—exists almost exclusively as a stable, constitutively active tetramer with rigid interfaces that preclude significant allosteric modulation. The liver-specific PKL and erythrocyte-specific PKR isoforms, both encoded by the PKLR gene, also form tetramers but display distinct sequence variations in their regulatory domains, adapting them to gluconeogenic (PKL) or non-proliferative (PKR) contexts with different sensitivities to activators like FBP. PKM2's propensity for interconversion between tetrameric and dimeric states underlies its allosteric flexibility, supporting roles in both glycolysis and non-metabolic processes in proliferating cells. Structural investigations since the early 2000s, primarily using X-ray crystallography, have elucidated these oligomeric transitions. For instance, the 2005 crystal structure of human PKM2 provided the foundational view of its tetrameric assembly and allosteric site. Subsequent studies in the 2010s, including analyses of mutant forms and post-translational modifications, revealed how disruptions at dimer or tetramer interfaces—such as the patient-derived K422R mutation—stabilize inactive conformations or promote dissociation, offering mechanistic insights into PKM2's dynamic regulation.

Biochemical Properties

Catalytic Mechanism

Pyruvate kinase M2 (PKM2) catalyzes the final step of glycolysis, transferring a phosphoryl group from phosphoenolpyruvate (PEP) to adenosine diphosphate (ADP) to produce pyruvate, adenosine triphosphate (ATP), and a proton, according to the reaction PEP + ADP + H⁺ → pyruvate + ATP.^[11] This irreversible reaction generates energy and is essential for ATP production in cells.^[12] The catalytic mechanism proceeds in two main steps. First, the phosphoryl group from PEP is directly transferred to ADP in an associative inline displacement, forming ATP and the enol tautomer of pyruvate; this step is facilitated by active site residues such as Lys269 (in rabbit muscle PK, homologous to Lys270 in human PKM2) that stabilize the transition state and orient the substrates, with no covalent phosphoenzyme intermediate involved.^[12] Second, the enol-pyruvate undergoes tautomerization to the stable keto form via proton abstraction, likely from a solvent-derived proton facilitated by conserved active site residues such as Thr328 and Ser362 (L. mesenteroides numbering; homologous in human PKM2), ensuring stereospecific protonation.^[11] Early mechanistic studies in the 1970s, building on work by Rose and Boyer, confirmed the absence of a phosphoenzyme intermediate through isotope exchange and stereochemical analyses, establishing the direct transfer and enolization steps.^[13] In PKM2, the active site architecture, including a bound potassium ion coordinating the substrates, supports this mechanism, though the core catalysis is conserved across pyruvate kinase isoforms.^[12] PKM2 exhibits Michaelis-Menten kinetics modulated by its oligomeric state, with the tetrameric form displaying high substrate affinity and the dimeric form showing low affinity. For PEP, the Michaelis constant (Km) is approximately 0.03 mM in the tetramer versus 0.5 mM in the dimer, while the maximum velocity (Vmax) remains comparable at around 300 U/mg protein across forms.^[14] Due to its allosteric properties, PKM2 deviates from simple hyperbolic kinetics and follows the Hill equation for cooperative binding:

v = \frac{V_{\max} [S]^n}{K_{0.5}^n + [S]^n}

where v is the reaction velocity, [S] is the substrate concentration (e.g., PEP), V_{\max} is the maximum velocity, K_{0.5} is the substrate concentration at half Vmax, and n is the Hill coefficient, typically 1.5–2 for PEP in the absence of activators, reflecting positive cooperativity.^[15] This cooperativity arises from intersubunit interactions in the tetramer, enabling sensitive regulation of glycolytic flux.^[9] The isoform specificity of PKM2 lies in its ability to interconvert between high-activity tetramers and low-activity dimers, unlike PKM1, which constitutively forms stable, high-affinity tetramers with a Km for PEP of about 0.03–0.1 mM and no cooperativity (n ≈ 1).^[16] In the low-activity dimeric state, PKM2's reduced catalytic efficiency limits pyruvate production, diverting upstream glycolytic intermediates toward biosynthetic pathways such as the pentose phosphate pathway for nucleotide and lipid synthesis, a feature critical for proliferating cells.^[9] This dynamic regulation contrasts with PKM1's constitutive high activity, which supports oxidative metabolism in differentiated tissues without favoring biosynthesis.^[16]

Allosteric Regulation

Pyruvate kinase M2 (PKM2) is subject to positive allosteric regulation primarily by fructose-1,6-bisphosphate (FBP), which binds at the interface of the C-domains in the tetrameric form, stabilizing the active conformation and promoting tetramerization with a dissociation constant (Kd) of approximately 1 nM (at pH 7.5).^[17] This binding enhances PKM2's catalytic activity by shifting the enzyme from the less active dimeric state to the highly active tetrameric state, thereby accelerating the final step of glycolysis.^[18] Additionally, tyrosine phosphorylation at residue Y105, often induced by oncogenic kinases such as fibroblast growth factor receptor 1, inhibits this FBP binding and tetramer formation, reducing PKM2 activity and favoring the dimeric form.^[19] Negative allosteric regulation of PKM2 involves amino acids such as phenylalanine and alanine, which strongly inhibit the dimeric form and suppress overall enzymatic activity by up to nearly 100% at physiological concentrations.^[20] Phenylalanine acts by binding to an allosteric site that locks PKM2 in a low-activity conformation, while alanine promotes dissociation into inactive dimers.^[18] Oxidative stress further modulates PKM2 through the formation of disulfide bonds, particularly involving cysteine residues Cys358 and Cys424; oxidation at these sites inhibits tetramer stability and enzymatic function, helping cells mitigate reactive oxygen species (ROS) accumulation.^[21] Post-translational modifications (PTMs) provide additional layers of allosteric control over PKM2. Acetylation at lysine 62 (K62), mediated by acetyltransferases and reversed by histone deacetylase 8 (HDAC8), alters the enzyme's conformational dynamics, influencing its metabolic and non-metabolic roles as identified in studies from the 2010s.^[22] Sumoylation, another key PTM, disassembles the PKM2 tetramer into monomers or dimers, thereby decreasing pyruvate kinase activity and promoting alternative cellular functions, such as in leukemia cell differentiation.^[23] Feedback loops involving upstream glycolytic intermediates, such as glucose-6-phosphate, indirectly regulate PKM2 through the PI3K/Akt pathway, where pathway activation enhances glycolytic flux and sustains PKM2's dimeric state to support biosynthetic demands.^[24] Recent insights from 2025 highlight succinyl-5-aminoimidazole-4-carboxamide ribose-5-phosphate (SAICAR), an intermediate in de novo nucleotide synthesis, as a novel allosteric activator of PKM2; SAICAR binding increases PKM2 affinity for its substrates, establishing crosstalk between glycolysis and purine biosynthesis to drive tumor cell proliferation.^[25]

Cellular Functions

Glycolytic Role

Pyruvate kinase M2 (PKM2) catalyzes the final rate-limiting step of glycolysis, transferring a phosphoryl group from phosphoenolpyruvate (PEP) to ADP to produce pyruvate and ATP. This reaction commits glycolytic intermediates to either mitochondrial oxidation via the tricarboxylic acid (TCA) cycle or conversion to lactate by lactate dehydrogenase A (LDHA), thereby controlling overall glycolytic flux and energy homeostasis. In cells with high PKM2 activity, such as the tetrameric form, pyruvate is efficiently directed toward mitochondrial import through the mitochondrial pyruvate carrier (MPC), supporting oxidative phosphorylation and maximal ATP yield of approximately 30-36 molecules per glucose molecule under normoxic conditions.^[2]^[26] In contrast, under hypoxic conditions or in proliferating cells, the less active dimeric form of PKM2 predominates, reducing glycolytic throughput at this step and favoring the accumulation of upstream intermediates for biosynthetic pathways. This modulation limits pyruvate production, shunting it primarily toward lactate via LDHA, which yields only 2 ATP per glucose but maintains redox balance through NAD+ regeneration and supports rapid cell division by diverting carbons to the pentose phosphate pathway (PPP) for nucleotide and NADPH synthesis. Such dynamics integrate PKM2 with mitochondrial metabolism, where reduced pyruvate import under low PKM2 activity decreases TCA flux and oxidative ATP production, adapting energy output to environmental constraints.^[27]^[26] The dimeric PKM2 configuration contributes to the Warburg effect by intentionally slowing glycolysis, which enables biomass accumulation essential for proliferating cells rather than prioritizing efficient energy harvest. This aerobic glycolysis phenotype, where cells produce lactate even in oxygen-rich environments, relies on PKM2's low catalytic efficiency to build metabolic intermediates for growth. Studies using metabolic flux models, including PKM2 knockout in mouse embryonic fibroblasts, demonstrate that loss of PKM2 leads to compensatory expression of PKM1, increased mitochondrial respiration, and reduced diversion to nucleotide biosynthesis, ultimately impairing proliferation.^[28] PKM2 interacts with upstream glycolytic enzymes like phosphofructokinase-1 (PFK1) through feedback mechanisms, where PFK1-generated fructose-1,6-bisphosphate (FBP) allosterically activates PKM2, forming a feed-forward loop that fine-tunes flux in response to cellular demands. In cancer cells, coordinated upregulation of PKM2 and LDHA by hypoxia-inducible factor-1α (HIF-1α) enhances this interplay, ensuring pyruvate availability for lactate production and sustaining the Warburg phenotype. PKM2 inhibition disrupts this coordination, reducing lactate output and glycolytic efficiency.^[29]^[30]

Non-Metabolic Roles

Beyond its enzymatic role in glycolysis, pyruvate kinase M2 (PKM2) has been proposed to exhibit protein kinase activity, particularly in its dimeric nuclear form, where it may phosphorylate signal transducer and activator of transcription 3 (STAT3) at tyrosine 705 (Y705). This phosphorylation has been suggested to enhance STAT3's transcriptional activity, promoting the expression of genes involved in cell proliferation and survival, such as MEK5, independent of traditional Janus kinase 2 (JAK2) or c-Src pathways.^[31] However, the protein kinase function of PKM2 remains controversial, with studies questioning its direct catalytic activity and attributing observed effects to indirect mechanisms like ATP regeneration.^[32] PKM2 has also been reported to interact with histones in the nucleus, potentially phosphorylating histone H3 at threonine 11 (T11) in a β-catenin-dependent manner, facilitating the recruitment of histone acetyltransferases like p300 and subsequent acetylation of nearby lysine residues, such as H3K18. This modification loosens chromatin structure at promoters of genes like CCND1, thereby linking glycolytic flux to epigenetic regulation and gene transcription essential for cell growth. The interaction between nuclear PKM2 and β-catenin is critical for this process, as disruption impairs histone phosphorylation and downstream acetylation, underscoring PKM2's influence on epigenetics.^[33] In the context of cell death regulation, PKM2 has been shown to bind to and potentially phosphorylate B-cell lymphoma 2 (Bcl-2) at threonine 69 (T69), stabilizing the anti-apoptotic protein and inhibiting caspase activation under oxidative stress conditions. This mitochondrial localization of PKM2 prevents cytochrome c release and apoptosis, providing a protective mechanism against cellular damage. Evidence for PKM2's multifunctionality is supported by structural studies, including crystal structures of dimeric PKM2 that reveal conformational flexibility enabling its protein interactions, distinct from its tetrameric glycolytic form.^[34] Investigations as of 2025 have further elucidated PKM2's role as a transcriptional co-regulator in inflammatory responses, where nuclear PKM2 has been linked to enhanced pro-inflammatory gene expression, such as interleukin-1β (IL-1β) and tumor necrosis factor alpha (TNF-α), exacerbating conditions like periodontitis and cytokine storms.^[35]^[36] This function positions PKM2 as a key integrator of metabolic reprogramming and immune signaling, with dimerization promoting its nuclear translocation.

Localization and Dynamics

Tissue and Cellular Distribution

PKM2 exhibits a distinct tissue distribution pattern, with elevated expression in organs associated with proliferation and biosynthetic demands, such as lung, adipose tissue, retina, and pancreas, while being minimally expressed in highly differentiated tissues like skeletal muscle and brain where the PKM1 isoform predominates.^[27]^[37] In contrast, PKM1 is the primary isoform in energy-demanding adult tissues including heart, liver, and nervous system, reflecting an adaptation for efficient ATP production in non-proliferative states.^[27] This differential distribution is regulated by alternative splicing of the PKM pre-mRNA, favoring PKM2 in contexts requiring metabolic flexibility.^[9] At the cellular level, PKM2 is predominantly expressed in proliferating cell types, including embryonic cells, stem cells, and fibroblasts, supporting rapid growth and nucleotide synthesis through glycolytic intermediates.^[37]^[38] During development, PKM2 is highly abundant in fetal tissues to accommodate biosynthetic needs, but expression shifts toward PKM1 in post-differentiation stages of most tissues, ensuring oxidative metabolism in mature cells.^[39] Quantitative analyses from the GTEx database reveal moderate to high mRNA levels of the PKM gene (encompassing both isoforms) across proliferative tissues like lung (median TPM ~48) and adipose (TPM ~26), with immunohistochemistry confirming stronger PKM2 protein staining in embryonic and proliferative normal tissues compared to differentiated ones.^[40]^[41]^[42] Recent studies highlight emerging roles for PKM2 in immune cells, particularly macrophages, where its expression increases under inflammatory conditions to reprogram metabolism toward anti-inflammatory responses, such as IL-10 production.^[43] PKM2 can promote M2 polarization in certain contexts, such as tumor-associated macrophages, but in models of liver and lung inflammation, it often drives pro-inflammatory M1 responses.^[44] This context-dependent expression underscores PKM2's adaptability in immune-mediated processes.^[45]

Subcellular Translocation

Pyruvate kinase M2 (PKM2) predominantly localizes to the cytoplasm under basal conditions, where it integrates into glycolytic complexes to facilitate efficient ATP production through the conversion of phosphoenolpyruvate to pyruvate. In these complexes, PKM2 directly interacts with and phosphorylates phosphoglycerate mutase 1 (PGAM1) at histidine 11 in a phosphoenolpyruvate-dependent manner, enhancing glycolytic flux and shunting intermediates toward biosynthetic pathways.^[46] This cytoplasmic association underscores PKM2's default role in metabolic regulation within the cytosol. Nuclear import of PKM2 is dynamically regulated and primarily occurs upon its dissociation from tetrameric to dimeric or monomeric forms, exposing a nuclear localization signal (NLS) in the C-terminal domain (residues 390–531). A key trigger is phosphorylation at serine 37 (S37) by extracellular signal-regulated kinase 2 (ERK2), activated downstream of epidermal growth factor receptor (EGFR) signaling, which induces a conformational change via prolyl isomerase PIN1, allowing binding to importin α5 for translocation into the nucleus.^[47]^[48] Additional phosphorylation events, such as at tyrosine 105 by fibroblast growth factor receptor 1 (FGFR1), further promote this import by stabilizing the dimeric state.^[48] Other stimuli from 2010s studies, including hypoxia, reactive oxygen species (ROS), and growth factors like insulin and insulin-like growth factor 1 (IGF1), also drive nuclear translocation through distinct pathways. Under hypoxia, the long non-coding RNA HIFAL interacts with PKM2 and prolyl hydroxylase domain-containing protein 3 (PHD3) to inhibit hydroxylation and promote nuclear entry.^[49] ROS oxidizes cysteine 423, shifting PKM2 to a nuclear-competent form, while growth factors activate ERK or AKT pathways to phosphorylate S37 or related sites.^[50] Nuclear export is mediated by checkpoint kinase 2 (Chk2)-dependent phosphorylation at serine 100, facilitating return to the cytoplasm, with deacetylation at lysine 433 by sirtuin 6 (SIRT6) aiding this process.^[50] In the nucleus, PKM2 supports transcriptional co-activation, contrasting its cytoplasmic metabolic enzymatic activity, thereby linking glycolysis to gene regulation based on compartmentalization. Recent 2025 evidence highlights PKM2's association with mitochondria under stress conditions, such as hypoxia or osteoarthritis, where it interacts with metallothionein 2A (MT2A) to maintain respiratory chain integrity or with the SIRT3-PINK1 axis to regulate mitophagy, adapting cellular metabolism to oxidative or inflammatory challenges.^[51]^[52]

Pathological Implications

Role in Cancer Metabolism

Pyruvate kinase M2 (PKM2) plays a pivotal role in the metabolic reprogramming of cancer cells, particularly through its contribution to the Warburg effect, where tumor cells preferentially undergo aerobic glycolysis even in the presence of oxygen. This isoform is overexpressed in most human cancers, including lung, colon, and renal cell carcinoma, with elevated levels observed across at least 16 tumor types compared to normal tissues.^[53] The upregulation of PKM2 is primarily driven by oncogenic transcription factors such as c-Myc, which promotes alternative splicing favoring the PKM2 isoform over PKM1 by enhancing the activity of splicing factors like hnRNP A1, A2, and PTB, and hypoxia-inducible factor 1 (HIF-1), which transactivates PKM2 expression via a hypoxia-response element while forming a positive feedback loop to amplify glycolytic gene transcription.^[53]^[26] This overexpression, first linked to the Warburg effect in studies from the 2000s, enables cancer cells to divert glycolytic intermediates toward biosynthetic pathways essential for rapid proliferation. In tumor cells, PKM2 predominantly exists in a low-activity dimeric form, which reduces pyruvate kinase activity and leads to the accumulation of upstream glycolytic intermediates such as phosphoenolpyruvate (PEP) and fructose-1,6-bisphosphate. This diversion enhances flux through the pentose phosphate pathway (PPP), generating NADPH for redox balance and ribose-5-phosphate for nucleotide synthesis, thereby supporting anabolic demands and protecting against oxidative stress in the hypoxic tumor microenvironment.^[53] The dimeric conformation is stabilized by post-translational modifications, including phosphorylation at tyrosine 105, further promoting this metabolic shift.^[54] PKM2 exhibits a bi-functional metabolic impact in cancer, where its low enzymatic activity in the dimeric state favors biosynthetic processes during proliferation, while activation to a high-activity tetrameric form under metabolic stress—such as nutrient deprivation—enhances glycolytic flux to ensure ATP production and cell survival.^[53] Experimental knockdown or knockout of PKM2 in cancer cell lines, such as H1299 lung carcinoma, reduces tumor growth in xenograft models by impairing this flexibility and diminishing the Warburg effect. In digestive system tumors, PKM2 overexpression is particularly prominent, with elevated levels in colorectal cancers that correlate with advanced staging and metastasis via enhanced glycolysis and PPP activity.^[54] Recent 2025 studies on gastric cancer highlight PKM2's role in a HIF-1α-mediated feedback loop that sustains aerobic glycolysis, while in colorectal models, it promotes tumor progression through OTUB2-stabilized dimers diverting metabolites to lipid synthesis.^[54]

Mutations and Disease Associations

Mutations in the PKM2 gene, particularly the missense variants H391Y and K422R, have been identified in patients with Bloom syndrome, a condition predisposing individuals to cancer. These mutations occur within the inter-subunit contact domain of the PKM2 protein, disrupting the formation of the active tetrameric structure and favoring dimerization instead. As a result, they exert a dominant-negative effect on wild-type PKM2, significantly reducing overall pyruvate kinase enzymatic activity and altering allosteric regulation, which diminishes responsiveness to activators like fructose-1,6-bisphosphate.^[55]^[56] The functional consequences of these cancer-associated PKM2 mutations include enhanced cellular proliferation and aggressive metabolic reprogramming toward the Warburg effect, even in the presence of wild-type PKM2. Cells co-expressing mutant and wild-type PKM2 exhibit increased anchorage-independent growth, oxidative endurance, and tumor formation in vivo, highlighting the mutations' role in promoting carcinogenesis through impaired glycolysis and non-metabolic signaling. Studies from the mid-2010s, including structural analyses, confirmed that these variants form aberrant hydrogen bonds at the dimer interface, stabilizing inactive conformations and thereby boosting oncogenic potential.^[57]^[58]^[59] Beyond cancer, PKM2 variants and dysregulation are implicated in neurodegenerative diseases such as Alzheimer's disease (AD). Elevated PKM2 expression in AD models correlates with increased amyloid-β (Aβ) production via regulation of γ-secretase activity, particularly under hypoxic conditions that mimic disease pathology. Moreover, PKM2 undergoes pH-sensitive aggregation into amyloid-like structures during cellular stress and aging, impairing glycolytic flux and contributing to neuronal dysfunction and memory impairment.^[60]^[61] In the context of diabetes, PKM2 plays a critical role in pancreatic β-cell proliferation, insulin secretion, and oscillatory glycolysis; loss-of-function or inhibition of PKM2 disrupts ATP production and impairs glucose-stimulated insulin release, linking its variants to β-cell dysfunction in type 2 diabetes pathogenesis.^[60]

Interactions in Bacterial Pathogenesis

PKM2 has been implicated in host-pathogen interactions during bacterial infections, particularly through its role in facilitating bacterial entry and nutrient acquisition. In the case of Neisseria gonorrhoeae, opacity-associated (Opa) proteins on the bacterial surface bind to PKM2 exposed on host epithelial cells, such as those in the HeLa cervical carcinoma line. This interaction promotes bacterial invasion by enabling intracellular gonococci to colocalize with cytoplasmic PKM2, creating a pyruvate-rich microenvironment essential for bacterial growth and survival, as pyruvate is a required nutrient for N. gonorrhoeae.^[62]^[6] Similarly, PKM2 influences pathogenesis in Salmonella typhimurium infections by modulating host macrophage responses. In activated macrophages, PKM2 interacts with hypoxia-inducible factor 1α (HIF-1α) to regulate IL-1β production, a key proinflammatory cytokine; activation of PKM2 suppresses IL-1β while enhancing anti-inflammatory IL-10, thereby dampening the immune response and increasing bacterial dissemination and replication within the host. This process involves a metabolic shift toward aerobic glycolysis in host cells, which PKM2 drives to favor pathogen survival over robust immunity.^[63] Mechanistically, bacterial infections can induce surface exposure of PKM2 on host cells, allowing direct binding by pathogens like N. gonorrhoeae Opa proteins and potentially aiding adhesion and invasion. Inhibition of PKM2 activity disrupts these interactions; for instance, pharmacological activation of PKM2 exacerbates Salmonella replication, while strategies to inhibit its non-glycolytic functions reduce bacterial loads by restoring proinflammatory signaling. Broader roles include PKM2's involvement in macrophage metabolic reprogramming during infections, where its dimer form promotes a glycolytic shift that supports pathogen persistence by limiting oxidative phosphorylation and reactive oxygen species production.^[62]^[63]^[64] Initial discoveries of PKM2's role in bacterial interactions date to the late 1990s, with the identification of Opa-PKM2 binding in gonococcal invasion.^[62]

Therapeutic and Diagnostic Potential

Clinical Biomarkers

PKM2, particularly its dimeric form known as tumor M2-pyruvate kinase (tM2-PK), serves as a non-invasive biomarker in serum and stool for detecting various malignancies. The tM2-PK assay measures the inactive dimeric isoform prevalent in tumor cells, offering higher sensitivity than traditional markers like carcinoembryonic antigen (CEA) for early cancer detection.^[65] In colorectal cancer (CRC), the serum tM2-PK assay demonstrates a sensitivity of approximately 80% and specificity around 75-90%, making it a valuable tool for screening and monitoring disease progression. Meta-analyses confirm its diagnostic accuracy, with pooled sensitivity of 82.4% and specificity of 78.6% across multiple studies, outperforming fecal occult blood tests in detecting both advanced and early-stage tumors. For breast cancer, serum tM2-PK levels exhibit sensitivity up to 85% in monitoring treatment response and detecting recurrence, providing complementary information to CA 15-3.^[66]^[67]^[68] Positron emission tomography (PET) imaging with tracers targeting PKM2, such as [18F]DASA-23, enables visualization of tumor glycolysis and PKM2 expression in vivo. This tracer has shown promise in clinical trials for glioblastoma and other solid tumors, with high uptake in PKM2-overexpressing lesions, facilitating non-invasive assessment of tumor metabolism and therapeutic response. Ongoing studies validate its utility in distinguishing malignant from benign tissues.^[69]^[70] Elevated PKM2 expression correlates with poor prognosis in lung cancer, as evidenced by meta-analyses of approximately 2,000 patients across solid cancers including lung showing high PKM2 levels associated with reduced overall survival (hazard ratio 1.73). In non-small cell lung cancer, high PKM2 expression is associated with poorer prognosis in lung adenocarcinoma.^[71]^[72] Beyond oncology, serum and fecal tM2-PK levels are elevated in inflammatory bowel disease (IBD), serving as a marker for disease activity and mucosal inflammation. In Crohn's disease and ulcerative colitis, tM2-PK concentrations correlate with endoscopic scores, aiding non-invasive monitoring and differentiation from irritable bowel syndrome.^[73]^[74] The tM2-PK assay, CE-marked and commercially available since the early 2010s, has undergone extensive validation through clinical trials and meta-analyses. Recent 2025 meta-analyses reaffirm its diagnostic utility for CRC and other gastrointestinal cancers, with area under the curve values exceeding 0.85 in receiver operating characteristic analyses.^[67]^[75]

Targeting Strategies

Targeting strategies for pyruvate kinase M2 (PKM2) primarily focus on small-molecule modulators that exploit its allosteric regulation to shift between dimeric (low-activity, tumor-promoting) and tetrameric (high-activity) forms, aiming to disrupt cancer cell metabolism and non-metabolic functions. Activators such as TEPP-46 and DASA-58 stabilize the tetrameric conformation of PKM2, enhancing its enzymatic activity and suppressing tumorigenesis in preclinical models. For instance, TEPP-46 has been shown to reduce xenograft tumor growth in mice by promoting tetramer formation and increasing pyruvate kinase activity, thereby redirecting glycolytic flux away from biosynthetic pathways that support proliferation. Similarly, DASA-58 induces PKM2 tetramerization in breast cancer cells, leading to metabolic reprogramming without compromising cell viability in vitro. These compounds, developed in the 2010s, highlight the potential of allosteric activation to inhibit tumor progression by countering the Warburg effect.^[38]^[76]^[77] In contrast, PKM2 inhibitors like shikonin and compound 3k target the dimeric form, particularly its nuclear translocation and transcriptional roles that drive oncogenesis. Shikonin, a naphthoquinone derivative, inhibits PKM2 nuclear localization, thereby blocking its interaction with transcription factors and reducing hypoxic induction of glycolytic genes such as PFKFB3 in cancer cells. Compound 3k, a more selective synthetic analog, disrupts PKM2 tetramer stability and promotes apoptosis in ovarian cancer cells by interfering with its nuclear functions, exhibiting nanomolar potency superior to shikonin. As of 2025, these inhibitors remain largely in preclinical stages, with limited clinical trials directly targeting PKM2 due to challenges in achieving specificity; however, shikonin derivatives are being explored in combination therapies for hepatocellular carcinoma to enhance sorafenib efficacy.^[78]^[79]^[80]^[81]^[82] Beyond small molecules, alternative strategies include allosteric site-targeted drugs and nucleic acid-based approaches to modulate PKM2 expression and isoform switching. Allosteric regulators bind sites distinct from the active center, such as those influenced by fructose-1,6-bisphosphate, to fine-tune PKM2 activity and prevent dimer formation in tumors. Gene therapy-like interventions, such as antisense oligonucleotides (ASOs), promote splice-switching from the oncogenic PKM2 to the constitutive PKM1 isoform, reversing the Warburg effect and inhibiting hepatocellular carcinoma growth in mouse models. These ASOs, including constrained-ethyl variants, demonstrate potent isoform redirection in vitro and in vivo, offering a targeted means to correct aberrant splicing without genomic integration.^[18]^[17]^[83]^[84] A key challenge in PKM2 targeting is achieving isoform specificity, as PKM2 shares high structural homology with PKM1 and other pyruvate kinase isoforms expressed in normal tissues, risking off-target effects like metabolic disruption in non-cancerous cells. For example, inhibitors designed for PKM2 may inadvertently affect PKM1, leading to unintended glycolytic inhibition in healthy tissues. Strategies to mitigate this include structure-based drug design focusing on unique allosteric pockets in PKM2. As of 2025, advances in targeted protein degradation, such as PROTACs, are emerging for metabolic enzymes in solid tumors, though specific PKM2 degraders remain in early discovery phases without reported clinical progress.^[85]^[86]^[22]^[87]

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Mar 6, 2014 · The story began a year or two ago, when two groups reported the surprising ability of PKM2 to function as a protein kinase (Gao et al., 2012, ...
[9]
PKM2, function and expression and regulation - Cell & Bioscience
Jun 26, 2019 · There have been many studies pointing out that PKM2 can be highly expressed in lung cancer, liver cancer, glioma, kidney cancer, etc., and there ...
[10]
Pyruvate kinase M2 regulates glucose metabolism by functioning as ...
HIF-1α is overexpressed in solid tumors due to intratumoral hypoxia, genetic alterations, or both [12, 18, 22, 23], and thus may be a predominant regulator that ...Hif-1 And Metabolic... · Regulation Of Pkm2... · Pkm2 And The Warburg Effect...
[11]
Pyruvate kinase: function, regulation and role in cancer - PMC - NIH
Pyruvate kinase is an enzyme that catalyzes the conversion of phosphoenolpyruvate and ADP to pyruvate and ATP in glycolysis and plays a role in regulating cell ...3. Pyruvate Kinase Genes... · 4. The Role Of Pkm2 In... · 4.2 Pkm2 Favors Anabolic...
[12]
Pyruvate kinase - M-CSA Mechanism and Catalytic Site Atlas
Pyruvate kinase catalyses the final step of glycolysis and is allosterically regulated by fructose-1,6-bisphosphate. It requires two equivalents divalent ...Reference Protein And... · Enzyme Reaction (ec:2.7. 1... · Enzyme Mechanism
[13]
https://www.jbc.org/article/S0021-9258(20)81816-X/pdf
[14]
Evidence That Does Not Support Pyruvate Kinase M2 (PKM2)
The Vmax of PKM2 dimer and tetramer is comparable, but the Km value of the dimer and tetramer toward PEP is 0.5 and 0.03 mm, respectively (33).Missing: Km Vmax
[15]
Cancer-associated mutations in human pyruvate kinase M2 ... - PMC
Feb 1, 2021 · PKM2 R399E exhibits increased cooperativity with respect to PEP (nH=1.3) in the absence of FBP when compared to wild-type PKM2 (Table 1).
[16]
PKM2 isoform-specific deletion reveals a differential requirement for ...
PKM1 and PKM2 differ by 22 amino acids and have distinct regulatory properties (Mazurek, 2011). While PKM1 forms a stable, constitutively active tetramer, PKM2 ...
[17]
Structural basis for allosteric regulation of pyruvate kinase M2 by ...
The structure of PKM2 S37E/K433E was solved using chain C of the PKM2-cysteine structure (PDB entry 6NU1) as a starting model. Iterative rounds of ...Missing: 3BJ8 | Show results with:3BJ8
[18]
Functional cross-talk between allosteric effects of activating and ...
Jul 2, 2019 · Initial velocity curves were fitted using Michaelis-Menten kinetics and the absolute concentration of PKM2 in the lysates was estimated ...
[19]
Oncogenic kinase-induced PKM2 tyrosine 105 phosphorylation ...
Treatment with the ErbB2 kinase inhibitor lapatinib decreased PKM2-Y105 phosphorylation and cancer stem-like cells, impeding PKM2 tumor-promoting function.
[20]
An allostatic mechanism for M2 pyruvate kinase as an amino-acid ...
The A-domain and C-domain correspond to the rigid body core of PYK. The active site is formed by a pocket between the rigid body core and the flexible B-domain.Missing: ABC lid<|control11|><|separator|>
[21]
Comprehensive analyses of the cysteine thiol oxidation of PKM2 ...
Apr 16, 2021 · These results highlight the possibility that PKM2 inhibition via Cys358 and Cys424 oxidation contributes to eliminating excess ROS and oxidative stress.
[22]
Pyruvate Kinase M2 Links Metabolism and Epigenetics - MDPI
Through various post-translational modifications, PKM2 can transform from a tetramer to a dimer, enter the cell nucleus, promote gene synthesis, and exert non- ...
[23]
SUMOylation disassembles the tetrameric pyruvate kinase M2 to ...
Jan 20, 2021 · Our results establish PKM2 as an essential modulator of leukemia cell differentiation and a potential therapeutic target.Missing: K62 | Show results with:K62
[24]
The PI3K/Akt Pathway and Glucose Metabolism - NIH
Recent evidence suggests that the PI3K/Akt signaling plays a fundamental role in promoting the so-called aerobic glycolysis or Warburg effect.Missing: loops | Show results with:loops
[25]
Pyruvate Kinase M1/2 Proteoformics for Accurate Insights into ... - PMC
Mar 16, 2025 · The direct binding of SAICAR to PKM2 enhances the affinity of PKM2 ... nucleotide synthesis metabolism, ultimately driving tumor cell ...
[26]
PKM2, a Central Point of Regulation in Cancer Metabolism - PMC
The PKM2 dimer has a higher K m towards PEP than the tetramer and thus is less active in converting PEP to ATP and pyruvate [19, 20].
[27]
Pyruvate Kinase M2 and Cancer: The Role of PKM2 in Promoting ...
Mar 1, 2020 · PKM2 promotes tumor angiogenesis by regulating HIF-1α through NF-κB activation. Mol Cancer. (2016) 15:3. doi: 10.1186/s12943-015-0490-2.
[28]
New roles for pyruvate kinase M2: working out the Warburg effect - NIH
Although PKM2 can clearly contribute to the development of aerobic glycolysis and the Warburg effect, it nevertheless remains unclear precisely how this ...
[29]
Glucose Catabolism in Liver Tumors Induced by c-MYC Can Be ...
Finally, knockout of PKM2 in mouse embryonic fibroblasts resulted in compensatory expression of PKM1, diversion of glucose flux from nucleotide biosynthesis ...Decreased Pkm2 Expression... · Silencing Of Pkm2 Expression... · Increasing Pkm1/pkm2 Ratio...
[30]
Mammalian target of rapamycin up-regulation of pyruvate kinase ...
Therefore, mTOR regulation of PKM2 through induction of HIF1α in part explains why cancer cells undergo glycolysis even under normoxic conditions. PKM2 is an ...Results · Mtor Is A Positive Regulator... · Mtor Stimulates Pkm2...
[31]
Emerging roles and the regulation of aerobic glycolysis in ...
Jul 6, 2020 · The PI3K/Akt signaling pathway can regulate the glycolysis in HCC through the following mechanisms. Firstly, activation of the PI3K/Akt ...
[32]
PKM2's Dual Role in Periodontitis: Regulating Inflammation and ...
Aug 24, 2025 · A recent study has confirmed that PKM2 enhances the secretion of inflammatory factors (such as IL-1β and TNF-α), increases lactate production, ...Missing: coactivation | Show results with:coactivation
[33]
Pyruvate Kinase Isoform Expression Alters Nucleotide Synthesis to ...
Jan 8, 2015 · PKM1 expression impairs nucleotide production and the ability to synthesize DNA and progress through the cell cycle.Missing: crosstalk | Show results with:crosstalk
[34]
Pyruvate kinase M2 activators promote tetramer formation and ... - NIH
Expression of the M2 isoform of pyruvate kinase (PKM2) can contribute to the characteristic glucose metabolism of tumors and replacement of PKM2 with its splice ...Missing: cryo- EM
[35]
PKM2, function and expression and regulation - PMC
Jun 26, 2019 · PKM2 binds to CD44 to inhibit phosphorylation of serine at a certain position in PKM2, inhibit promoting aerobic glycolysis and promoting ...
[36]
Tissue expression of PKM - Summary - The Human Protein Atlas
No readable text found in the HTML.<|separator|>
[37]
Discovery of functional alternatively spliced PKM transcripts in ...
Apr 18, 2019 · The transcript-expression level data of GTEx with 31 normal human tissues was downloaded from https://xenabrowser.net/datapages/?hub=https ...
[38]
Metabolic reprogramming of macrophages by PKM2 promotes IL-10 ...
Jan 7, 2025 · Macrophages play a crucial role in immune responses and undergo metabolic reprogramming to fulfill their functions.
[39]
Role of macrophage PKM2 in inflammation and tumor progression ...
Oct 14, 2025 · The regulation of macrophage polarization mediated by PKM2 emphasizes its importance as a central regulator of immune response and tumor ...
[40]
Ubiquitin-specific protease 7 regulates macrophage polarization via ...
Oct 27, 2025 · USP7 regulates macrophage polarization in SAP through PKM2-mediated metabolic reprogramming, providing novel insights into the therapeutic ...
[41]
PKM2 functions as a histidine kinase to phosphorylate PGAM1 ... - NIH
Here, PGAM1 activity is shown to be controlled by pyruvate kinase M2 (PKM2), promoting glycolytic shunts and macromolecule biosynthesis during metabolic ...
[42]
https://www.biorxiv.org/content/10.1101/613364v1.full-text
[43]
https://www.cell.com/cell-reports/fulltext/S2211-1247%2824%2901523-7
[44]
https://www.sciencedirect.com/science/article/pii/S0304419X25002203
[45]
https://www.nature.com/articles/s41419-025-08081-2
[46]
Hypoxia-induced MT2A-tetrameric PKM2 interaction maintains ...
Sep 24, 2025 · Mitochondrial metabolic reprogramming is a key step in the process of cellular adaptation to hypoxic stress for tumor growth, but the regulatory ...
[47]
Review Pyruvate kinase M2 and cancer: an updated assessment
Aug 19, 2014 · Upregulation of c-Myc expression by PKM2 forms a feed-forward loop, since c-Myc has been shown to upregulate transcription of heterogeneous ...
[48]
PKM2-driven metabolic reprogramming in digestive system tumors
Aug 6, 2025 · Activated PKM2 promotes aerobic glycolysis, markedly increasing glucose consumption and lactate production, particularly under glucose-starved ...
[49]
Missense mutations in pyruvate kinase M2 promote cancer ...
Interestingly, cells co-expressing PKM2 and mutant (K422R or H391Y) showed significantly aggressive cancer metabolism as compared with cells expressing either ...
[50]
Impact of Cancer-Associated PKM2 Mutations on Enzyme Activity ...
PKM2 is kinetically active in its tetrameric form, with reduced activity in its dimeric and monomeric states. (37) After evaluating ligand binding affinity and ...
[51]
Missense Mutations in Pyruvate Kinase M2 Promote Cancer ...
Interestingly, cells co-expressing PKM2 and mutant (K422R or H391Y) showed significantly aggressive cancer metabolism as compared with cells expressing either ...
[52]
PKM2 and cancer: The function of PKM2 beyond glycolysis - PMC
Missense mutations in the PKM2 gene, including H391Y and K422R, are observed within the inter-subunit contact domain of the PKM2 protein, which may promote ...
[53]
Structural insight into mechanisms for dynamic regulation of PKM2
... tetramer to adopt an R-state conformation (Fig. 3). The PKM2K422R tetramer is structurally similar to the PKM2Phe tetramer (PDB: 4FXJ) with a rmsd of 0.41 Å ...
[54]
Aberrant role of pyruvate kinase M2 in the regulation of gamma ...
Dec 7, 2021 · These findings indicate that PKM2 is an important gamma-secretase regulator that promotes Aβ production and memory impairment under hypoxia.
[55]
PKM2 aggregation drives metabolism reprograming during aging ...
Jul 9, 2024 · We find that PKM2 forms aggregates in senescent cells and organs from aged mice, impairing its enzymatic activity and glycolytic flux, thereby driving cells ...
[56]
Activation of pyruvate kinase as therapeutic option for rare hemolytic ...
This review will highlight the role of PK in hereditary hemolytic anemias, thereby providing a rationale for PK activators in the treatment of these diseases.
[57]
ROLE OF PYRUVATE KINASE IN CANCER AND HEMOLYTIC ...
Sep 10, 2025 · The pyruvate kinase enzyme regulates the final step of glycolysis by converting phosphoenolpyruvate to pyruvate or lactate while producing ATP.<|control11|><|separator|>
[58]
https://pmc.ncbi.nlm.nih.gov/articles/PMC4774429/
[59]
Pyruvate kinase M2 regulates Hif-1α activity and IL-1β ... - PubMed
Jan 6, 2015 · Finally, activation of PKM2 by TEPP-46 in vivo inhibited LPS and Salmonella typhimurium-induced IL-1β production, while boosting production of ...
[60]
Pyruvate Kinase M2: A Potential Target for Regulating Inflammation
We here review the current literature on PKM2 and its regulation, and discuss the potential for this protein as a therapeutic target in inflammatory disorders.
[61]
Microbial metabolites in tumor metabolic reprogramming ... - Frontiers
Pyruvate kinase M2 (PKM2), a critical rate-limiting enzyme in the final step of glycolysis, catalyzes the conversion of phosphoenolpyruvate (PEP) to pyruvate ...
[62]
Serum M2-pyruvate kinase: A promising non-invasive biomarker for ...
Clinical studies indicate that serum M2-PK has a higher sensitivity than serum carcinoembryonic antigen (CEA), is a valuable tumor marker in detection of ...Missing: PKM2 breast
[63]
Diagnostic value of pyruvate kinase isoenzyme type M2 ... - PubMed
Sep 26, 2025 · This meta-analysis showed that M2-PK has a relatively high sensitivity and specificity for diagnosing CRC and has a higher diagnostic value ...
[64]
Diagnostic value of pyruvate kinase isoenzyme type M2 for...
Sep 26, 2025 · Therefore, we made a meta-analysis from published trials to investigate the value of tumor M2-PK as a biomarker for the diagnosis of CRC. The ...
[65]
Tumor M2 pyruvate kinase – determination in breast cancer patients ...
U/ml, for tumor M2-PK and CA 15-3, respectively, 17 of the 20 patients (85%) were considered 'tumor M2-PK sensitive' and 15 of the 20 patients (75%) were ...
[66]
A Clinical PET Imaging Tracer ([18F]DASA-23) to Monitor Pyruvate ...
Pyruvate kinase M2 (PKM2) catalyzes the final step in glycolysis, a key process of cancer metabolism. PKM2 is preferentially expressed by glioblastoma (GBM) ...
[67]
A Clinical PET Imaging Tracer ([18F]DASA-23) to Monitor Pyruvate ...
Pyruvate kinase M2 (PKM2) catalyzes the final step in glycolysis, a key process of cancer metabolism. PKM2 is preferentially expressed by glioblastoma (GBM) ...
[68]
Pyruvate kinase M2 (PKM2) expression correlates with prognosis in ...
Jan 3, 2017 · In addition, subgroup analyses showed that elevated PKM2 levels predicted the poor prognosis for solid cancer patients, regardless of data ...
[69]
PKM2 is a potential prognostic biomarker and related to immune ...
Dec 14, 2023 · Prognostic analysis indicated that high expression of PKM2 was associated with poorer prognosis in overall lung cancer patients, especially in lung ...
[70]
Elevation of serum pyruvate kinase M2 (PKM2) in IBD and ... - PubMed
We aimed to assess levels of serum PKM2 in healthy and newly diagnosed IBD patients and its relationship with IBD indices and microbiota changes.Missing: monitoring | Show results with:monitoring
[71]
Targeting Immune Cell Metabolism in the Treatment of Inflammatory ...
Mar 10, 2021 · Serum and fecal samples from patients with IBD have shown high levels of pyruvate kinase M2 (PKM2), which has been proposed as a potential serum ...
[72]
Tumor M2-PK - Wikipedia
Tumor M2-PK is a synonym for the dimeric form of the pyruvate kinase isoenzyme type M2 (PKM2), a key enzyme within tumor metabolism.Missing: clinical assay serum
[73]
Diagnostic value of pyruvate kinase isoenzyme type M2 for ...
Oct 3, 2025 · Conclusion This meta-analysis showed that M2-PK has a relatively high sensitivity and specificity for diagnosing CRC and has a higher diagnostic ...
[74]
Pyruvate kinase M2 activators suppress tumour formation - ecancer
Aug 31, 2012 · Tumours in mice treated with TEPP-46 were significantly smaller and slower growing than those in control mice treated with vehicle; furthermore, ...Missing: tumor | Show results with:tumor
[75]
Pharmacological activation of pyruvate kinase M2 reprograms ... - NIH
Jan 22, 2021 · In this study, we show that DASA-58 can induce pyruvate kinase activity in breast cancer cells without affecting the overall cell survival.Missing: preclinical | Show results with:preclinical<|separator|>
[76]
PKM2 dictates the poised chromatin state of PFKFB3 promoter to ...
Shikonin inhibits the nuclear translocation of PKM2 to hamper hypoxic induction of PFKFB3. PKM2 is associated with various non-canonical functions that drive ...
[77]
Targeting PKM2 in cancer therapeutics: mechanistic advances and ...
Gastric cancer (GC) remains one of the most prevalent and lethal malignancies of the digestive system. PKM2 has been identified as a key regulator in GC ...
[78]
Discovery of novel naphthoquinone derivatives as inhibitors of the ...
Sep 29, 2017 · Compound 3k showed more potent PKM2 inhibitory activity than the positive control shikonin. •. Compound 3k exhibited nanomolar antitumor ...<|separator|>
[79]
Specific Pyruvate Kinase M2 Inhibitor, Compound 3K, Induces ...
Here, we investigated the anticancer effects of compound 3K, a specific PKM2 inhibitor, on the regulation of autophagic and apoptotic pathways in SK-OV-3.Missing: 2025 | Show results with:2025
[80]
Pyruvate Kinase M2 Links Metabolism and Epigenetics
Sep 17, 2025 · Shikonin and compound 3k are considered effective PKM2 inhibitors ... However, clinical trials for PKM2 therapy are still insufficient, and ...
[81]
ASO-Based PKM Splice-Switching Therapy Inhibits Hepatocellular ...
Antisense oligonucleotides are used to induce a change in PKM isoform usage in hepatocellular carcinoma, reversing the Warburg effect and inhibiting.
[82]
ASO-based PKM splice-switching therapy inhibits hepatocellular ...
In this study, we investigated the efficacy of ASO-based PKM splice-switching as a targeted therapy for liver cancer, using cell-culture and mouse models. We ...
[83]
Identification of small molecule inhibitors of pyruvate kinase M2 - NIH
To test the effects of PKM2 inhibition on cancer cells, Compound 3 was added to H1299 human lung cancer cells. H1299 cells are known to express PKM2 as their ...
[84]
Identification of small molecule inhibitors of pyruvate kinase M2
Apr 15, 2010 · One potential challenge for identifying a small molecule that selectively inhibits PKM2 is the similarity between PKM2 and the other isoforms ...
[85]
PKM2-driven metabolic reprogramming in digestive system tumors
Aug 5, 2025 · PKM2 also catalyzes phosphorylation of phosphoglycerate mutase 1 (PGAM1) at histidine 11, which enhances aerobic glycolysis and promotes tumor ...