Pyruvate Kinase M2 and Cancer: The Role of PKM2 in Promoting Tumorigenesis

Abstract

Pyruvate kinase plays a pivotal role in regulating cell metabolism. The final and rate-limiting step of glycolysis is the conversion of Phosphoenolpyruvate (PEP) to Pyruvate, which is catalyzed by Pyruvate Kinase. There are four isomeric, tissue-specific forms of Pyruvate Kinase found in mammals: PKL, PKR, PKM1, and PKM2. PKM1 and PKM2 are formed bya single mRNA transcript of the PKM gene by alternative splicing. The oligomers of PKM2 exist in high activity tetramer and low activity dimer forms. The dimer PKM2 regulates the rate-limiting step of glycolysis that shifts the glucose metabolism from the normal respiratory chain to lactate production in tumor cells. Besides its role as a metabolic regulator, it also acts as protein kinase, which contributes to tumorigenesis. This review is focused on the metabolic role of pyruvate kinase M2 in normal cells vs. cancerous cells and its regulation at the transcriptional level. The review also highlights the role of PKM2 as a potential diagnostic marker and as a therapeutic target in cancer treatment.

Simultaneous Combination of the CDK4/6 Inhibitor Palbociclib With Regorafenib Induces Enhanced Anti-tumor Effects in Hepatocarcinoma Cell Lines

“…PKM2 is another moonlighting glycolytic enzyme that exerts nuclear-related pro-proliferative functions when maintained in the less active dimeric form through phosphorylation at Tyr 105 (47). Palbociclib and regorafenib combination reduced phospho-PKM2 Tyr105 levels.…”

“…In contrast, the expression of aldolase A, which is up-regulated in HCC tissues and correlates with HCC malignancy (46), was significantly decreased by the combination in comparison with control or single agent treatments (Figure 7C). Then, we investigated the activation/expression of pyruvate kinase M2 (PKM2), which is predominantly expressed as a dimeric form with low PK activity in cancer cells (47). As shown in Figure 7D, palbociclib and regorafenib alone or in combination had no effect on PKM2 protein expression, but decreased its phosphorylation at Tyr 105 , presumably favoring the switch from the low active dimer to the highly active tetrameric form of the enzyme (48).…”

Protein kinase function of pyruvate kinase M2 and cancer

“…PKM2 is involved in many pathological processes of numerous tumor types such as gastrointestinal cancer, hepatocellular carcinoma and lung cancer. PKM2 can promote tumor growth, metastasis and chemo-resistance by directly regulating tumor cell metabolism as an enzyme or regulating different signaling pathways as a nuclear transcription cofactor [ 38 , 39 ]. For example, PKM2 promotes tumor growth and suppresses cell apoptosis through regulating Bcl-xL transcription in gastric cancer cells [ 40 ] or regulating NF-κB/p65 and HIF-1α activation [ 18 ] and mitogen-activated protein kinases (MAPKs) [ 41 ] in pancreatic tumor cells.…”

Compound 3K, a Specific Pyruvate Kinase M2 Inhibitor, Induces Autophagic Cell Death through the Disruption of the Glycolytic Pathway in Ovarian Cancer Cells

“…In this study, treatment with compound 3K caused an arrest of the cells at the G2/M phase, which was mediated by an increase in the expression of p-Cdc2. Moreover, PKM2 plays an important role in the pathways associated with metastasis [7]. SiRNA-mediated knockdown of PKM2 resulted in an upregulation of tumor suppressors, including Bad, caspase 7, and E-cadherin, whereas oncogenes, such as MMP-2, MMP-9, HIF1α, and VEGF, were downregulated in the SK-OV-3 cells [15].…”

“…Besides metabolic reprograming, PKM2 acts as a protein kinase transcriptional coactivator of genes that influence cell proliferation, apoptosis, and migration [6,7]. In the cellular environment, PKM2 is mechanistically associated with the mammalian target of rapamycin (mTOR)/protein kinase B (Akt) signaling pathway, which is associated with various cellular processes, including cell survival and growth, protein synthesis, cell cycle progression, and angiogenesis [8].…”