PKM2, STAT3 and HIF-1α: The Warburg’s vicious circle

The M2 isoform of pyruvate kinase, highly expressed in tumor cells, is known to engage a feed forward loop with the glycolysis master transcription factor HIF-1a. Gao and co-authors recently showed that dimeric PKM2 localizes to the nucleus in highly proliferating cancer cells, where it regulates in vivo growth by acting as a protein kinase and directly activating STAT3. STAT3 is therefore a novel player of the PKM2/HIF-1a feedback loop, since HIFinduced PKM2 activates STAT3 that in turn induces HIF-1a expression. These findings have profound implications for understanding the complex connections between gene regulation, metabolism, survival and proliferation in cancer.