Modulation of M2‐type pyruvate kinase activity by the cytoplasmic PML tumor suppressor protein

Abstract

The promyelocytic leukemia (PML) tumor suppressor protein accumulates in PML nuclear bodies (PML‐NBs), and can induce growth arrest, cellular senescence and apoptosis. PML has also been localized in the cytoplasm, although its function in this localization remains elusive. A general property of primary cancers is their high glycolytic rate which results from increased glucose consumption. However, the mechanism by which cancer cells up‐regulate glycolysis is not well understood. Here, we have shown that cytoplasmic PML (cPML) directly interacts with M2‐type pyruvate kinase (PKM2), a key regulator of carbon fate. PKM2 determines the proportion of carbons derived from glucose that are used for glycolytic energy production. Over‐expression of PML‐2KA mutant in the cytoplasm, which was generated by mutagenesis of the nuclear localization signals of PML, in MCF‐7 breast cancer cells suppressed PKM2 activity and the accumulation of lactate. PKM2 exists in either an active tetrameric form which has high affinity for its substrate phosphoenolpyruvate (PEP) or a less active dimeric form which has low affinity for its substrate. Over‐expression of PML‐2KA suppressed the activity of the tetrameric form of PKM2, but not the dimeric form. Our findings suggest that cPML plays a role in tumor metabolism through its interaction with PKM2.