Germline loss of PKM2 promotes metabolic distress and hepatocellular carcinoma

Abstract

Alternative splicing of the Pkm gene product generates the PKM1 and PKM2 isoforms of pyruvate kinase (PK), and PKM2 expression is closely linked to embryogenesis, tissue regeneration, and cancer. To interrogate the functional requirement for PKM2 during development and tissue homeostasis, we generated germline PKM2-null mice (Pkm2). Unexpectedly, despite being the primary isoform expressed in most wild-type adult tissues, we found that Pkm2 −/− mice are viable and fertile. Thus, PKM2 is not required for embryonic or postnatal development. Loss of PKM2 leads to compensatory expression of PKM1 in the tissues that normally express PKM2. Strikingly, PKM2 loss leads to spontaneous development of hepatocellular carcinoma (HCC) with high penetrance that is accompanied by progressive changes in systemic metabolism characterized by altered systemic glucose homeostasis, inflammation, and hepatic steatosis. Therefore, in addition to its role in cancer metabolism, PKM2 plays a role in controlling systemic metabolic homeostasis and inflammation, thereby preventing HCC by a non-cell-autonomous mechanism.

Understanding the Intersections between Metabolism and Cancer Biology

“…PKM2 is an isoform of the glycolytic enzyme pyruvate kinase that is expressed in most cancers (Figure 2) and is regulated by oncogenic signaling (Israelsen and Vander Heiden, 2015). PKM2 expression is not required for growth of breast tumors, liver tumors, leukemia, or xenograft tumors from various human cancer cell lines in mice (Dayton et al, 2016; Israelsen and Vander Heiden, 2015). However, studies of PKM2 still provide insight into cancer metabolic regulation.…”

“…However, studies of PKM2 still provide insight into cancer metabolic regulation. PKM2 loss promotes cancer in some mouse models, and characterizing these models has argued that how glucose is metabolized can influence tumor progression (Dayton et al, 2016; Israelsen et al, 2013). In fact, activating PKM2 can slow growth of some tumors, but the ability of tumors to lose pyruvate kinase expression argues against PKM2 being a good therapeutic target for most cancers (Israelsen and Vander Heiden, 2015).…”

Pyruvate Kinase Inhibits Proliferation during Postnatal Cerebellar Neurogenesis and Suppresses Medulloblastoma Formation

“…However, isoform-specific deletion studies show that PKM2 is not required for tumor formation. Aged mice with isoform-specific Pkm2 deletion develop liver cancer (31) and breast cancers are accelerated in Brca1 -deleted mice with co-deletion of Pkm2 (32). These studies identify cancers in which Pkm2 deletion promotes tumor growth.…”

Homocysteine Activates B Cells via Regulating PKM2-Dependent Metabolic Reprogramming

“…Pyruvate kinase is a rate-limiting glycolytic enzyme and controls the last step of this pathway (13). Although PKM2 has been reported to be mainly expressed in tumor cells and embryonic cells (13,14), recent reports showed that PKM2 is the main pyruvate kinase isoform expressed in the mouse spleen (20,22). To test whether B cells, one of the major cell types in the spleen, express PKM2, we first measured the mRNA and protein levels of the pyruvate kinase isoforms expressed in B cells.…”

“…The expression of PKM2 in tumor cells allows for an increase in both glycolytic and anabolic metabolic rates to support cell growth and proliferation (14). There have been a few recent reports showing that PKM2 is also required for normal cells (17)(18)(19)(20). M1 macrophages upregulate PKM2 expression to increase glycolytic flux in support of cell activation (18,19).…”