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The Role of PKM2 in the Initiation and Maintenance of Bladder Cancer - Expert Commentary

Tumor cells frequently rewire their metabolism to satisfy increased demands for cellular building blocks. The relative abundance of pyruvate kinase M1 (PKM1) versus PKM2 mediated by alternative splicing of the Pkm gene has been implicated in the shift between oxidative phosphorylation and aerobic glycolysis. A recent study by Xia et al. in Cancer Research examined the role of PKM2 in urothelial cancer.  The investigators examined the effect of PKM2 silencing in oncogenic HRAS-driven urothelial cancer murine models. Silencing PKM2 in mouse urothelial cells did not affect tumor initiation but inhibited the growth and maintenance of HRAS-driven tumors. Pharmacologic inhibition of PKM2 recapitulated this phenotype.


The investigators then examined the effects of PKM2 inhibition on the PKM2-STAT3-HIF1/VEGF signaling axis. Genetic and pharmacologic inhibition of PKM2 significantly inhibited the formation of PKM2-STAT3 complexes, their nuclear translocation, and angiogenesis mediated by HIF1 and VEGF. Nuclear STAT3 deficiency in the absence of PKM2 was similarly associated with impaired autophagy and increased apoptosis. Controlled PKM2 overexpression did not induce cancer in simple urothelial hyperplasia, but overexpression of PKM2, but not PKM1, in nodular urothelial hyperplasia with angiogenesis significantly accelerated carcinogenesis.

Finally, the investigators show that PKM2 is overexpressed in non-muscle-invasive and muscle-invasive bladder cancer patients. The investigators conclude that PKM2 is not necessary for cancer initiation but is required for tumor development and maintenance via angiogenesis and metabolic addiction. The investigators note that the RAS mutations and PKM2 over-expression are common events in patients with NMIBC cooperate to promote tumor growth and maintenance in humans via mechanisms similar to those described in these murine models.

Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine, New York City, New York

References:

  1. Xia Y, Wang X, Liu Y, Shapiro E, Lepor H, Tang MS, Sun TT, Wu XR. PKM2 is essential for bladder cancer growth and maintenance. Cancer Res. 2021 Dec 13:canres.CAN-21-0403-A.2021. doi: 10.1158/0008-5472.CAN-21-0403. Online ahead of print. PMID: 34903602
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