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Review
. 2020 Mar 2:10:159.
doi: 10.3389/fonc.2020.00159. eCollection 2020.

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

Kulsoom Zahra  1 , Tulika Dey  1 , Ashish  2 , Surendra Pratap Mishra  1 , Uma Pandey  3
Affiliations
Review

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

Kulsoom Zahra et al. Front Oncol. .

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.

Keywords: anaerobic glycolysis; angiogenesis; cancer metabolism; chemotherapy; pyruvate kinase M2.

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Figures

Figure 1
Figure 1
Schematic diagram of glucose metabolism in healthy cells and cancer cells.
Figure 2
Figure 2
PKM2 exists in two isomeric forms: a highly active tetramer and a low-activity dimer, whereas PKM1 constitutively exists only as a highly active tetramer. Several molecules control the switching between the dimeric and tetrameric forms of PKM2. E7 oncoproteins, tyrosine kinase-mediated phosphorylation, acetylation, and oxidation encourage the formation of low-activity dimer PKM2. In contrast, fructose-1,6-P2, serine, and SAICAR promote the formation of highly active tetramer (18).
Figure 3
Figure 3
Under the hypoxic condition, translocation of PKM2 and p65 to the nucleus takes place. Upon interaction with PKM2, NF-kB subunit p65 activates the transcription of HIF-1α gene and its target gene, VEGF-A, in the nucleus. As a result, increased secretion of VEGF translates to increased blood vessel formation, contributing to tumor growth (55).
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