Increased PKM2 tetramerization and pyruvate kinase activity suppress tumorigenesis.

  • Major finding: Increased PKM2 tetramerization and pyruvate kinase activity suppress tumorigenesis.

  • Concept: Tumor-specific PKM2 expression may be due to selection against high pyruvate kinase activity.

  • Impact: PKM2 activators promote a metabolic state that is not conducive to biosynthesis and cell proliferation.

Increased nutrient uptake and altered metabolic pathways in cancer cells support the biosynthetic demands of a hyperproliferative state. Cancer cells preferentially express the M2 isoform of pyruvate kinase (PKM2), which catalyzes the last step of glycolysis. The relatively low pyruvate kinase activity of PKM2 compared with other pyruvate kinase isoforms facilitates the diversion of glycolytic metabolites into anabolic pathways that support rapid growth and proliferation. Because PKM2 is specifically expressed in proliferating cells, one possibility is that PKM2 expression is selected for during oncogenic transformation. However, Anastasiou and colleagues hypothesized that there is instead selection against high pyruvate kinase activity associated with the constitutively active PKM1 isoform expressed in many normal cells, suggesting that synthetic PKM2 activators might inhibit cancer cell proliferation. Consistent with this paradigm, forced expression of PKM1 in PKM2-expressing cancer cells increased total cellular pyruvate kinase activity and suppressed xenograft tumor growth. Furthermore, PKM2 activators stabilized the tetrameric active form of PKM2, increased pyruvate kinase activity, and reduced the rate of cancer cell proliferation under hypoxic conditions in association with decreased intracellular concentrations of biosynthetic intermediates. It is notable that one PKM2 activator, TEPP-46, was orally bioavailable and had favorable pharmacokinetic and pharmacodynamic properties in mice. Treatment with TEPP-46 was well tolerated, and similar to the effects seen in cultured cells, treatment of xenograft tumor-bearing mice with TEPP-46 increased tetramerization of PKM2 and decreased intratumoral levels of lactate, ribose phosphate, and serine compared with levels in vehicle-treated mice. Additionally, TEPP-46 treatment safely led to a significant delay in the formation of xenograft tumors and reduction in tumor burden. PKM2 activation may therefore represent a strategy to specifically target the altered metabolic state of cancer cells and suppress tumor growth.

Anastasiou D, Yu Y, Israelsen WJ, Jiang JK, Boxer MB, Hong BS, et al. Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis. Nat Chem Biol 2012 Aug 26 [Epub ahead of print].

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