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.

Pyruvate Kinase M2: Multiple Faces for Conferring Benefits on Cancer Cells

“…Various factors have been reported to control the switch between the dimeric and tetrameric forms of PKM2 (5,6,8,19,(36)(37)(38)(39)(40)(41)(42)(43)(44). For example, fructose-1,6-bisphosphate (fructose-1,6-P 2 ), a glycolytic intermediate, binds allosterically to PKM2 and facilitates the formation of the active tetramer.…”

“…A variety of molecules interact with PKM2 (5,6,8,14,18,19,21,23,24,28,(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60)(61)(62)(63)(64)(65). Many of them affect the glycolytic functions of PKM2, which directly regulate the Warburg effect.…”

Shikonin and its analogs inhibit cancer cell glycolysis by targeting tumor pyruvate kinase-M2

“…PK activity was calculated at 25 1C by monitoring change of absorbance at 340 nm from 0 to 20 min. The activity of PK here was defined as the quantity of NADH oxidized by 1 mg of lysate protein or recombinant human PKM2 per minute (Ikeda and Noguchi, 1998;Shimada et al, 2008;Vander Heiden et al, 2010). Human recombinant PKM2 was either purchased from BPS Bioscience Inc, with an attached datasheet of characterization (Supplementary Figure 22), or from an in-house source as described in the preceding sections.…”

ERK2-Pyruvate Kinase Axis Permits Phorbol 12-Myristate 13-Acetate-induced Megakaryocyte Differentiation in K562 Cells

“…The dimerization-tetramerization oscillation of PKM2 is a reversible process in normally dividing cells, which is regulated by the intracellular fructose 1,6-bisphosphate concentrations (20,21). Various studies based on post-translational modifications like tyrosine 105 phosphorylation (22), xenograft tumor model studies (23), and physical interaction of some proteins, such as Oct4 (24), PML (25), A-Raf (3), and pathogenic E7 (26,27) etc., have confirmed that reduced PKM2 activity promotes tumor progression (28). PKM2 dimer has also been demon-strated to act as a protein kinase and regulate gene transcription to affect important cellular functions (29).…”