The responsively decreased PKM2 facilitates the survival of pancreatic cancer cells in hypoglucose

Abstract

Cancer cells predominantly produce energy at a high rate of glycolysis even in aerobic environment. It is termed as Warburg effect and is necessary for the tumorigenesis. Studies showed pyruvate kinase M2 (PKM2), a key regulator of the Warburg effect, is overexpressed and involved in numerous cancers. However, the expression and function of PKM2 in pancreatic cancer (PC) remain undefined. Our results showed that PKM2 is overexpressed in the PC tissue compared to the peritumoral tissue. Unexpected, the downregulation of PKM2 did not affect the proliferation, invasion, and chemoresistance of PC cells. Since pancreatic cancer is a hypovascular tumor with comparably insufficient energy supply, we further investigate the relationship between PKM2 and hypoglucose. Interestingly, we further discovered that decreased expression of PKM2 was detected in PC samples with lower microvessel density as well as in PC cells treated with hypoglucose condition (0.5 mM). Furthermore, the downregulation of PKM2 facilitated, while the upregulation of PKM2 inhibited, PC cells survival during hypoglucose. We further revealed that the repressed PKM2 induced autophagy, high NADPH/NADP ratio, and biomacromolecule production, but reduced ROS accumulation. Moreover, AMPKα1 knockdown repressed the autophagy and survival of PC cells during hypoglucose, which were promoted by PKM2 knockdown. Collectively, our study indicates that decreased PKM2 diverts glucose metabolism to biomacromolecule accumulation and antioxidants generation during glucose deprivation. This metabolism alteration elevates AMPKα1-dependent autophagy, which facilitates PC cell survival during glucose deprivation. Therefore, functions of PKM2 are complicated and cannot be defined as oversimplified promoter or inhibitor in PC.

Cutting off the fuel supply to calcium pumps in pancreatic cancer cells: role of pyruvate kinase-M2 (PKM2)

“…Although PKM2 is reported to be highly oncogenic in numerous cancers, 14,15,[30][31][32][33] there are several strands of evidence from cell lines and genetically modified mouse models of different cancers that PKM2 deletion has no effect on cancer. 34,37,[55][56][57][58][59] More specifically, a recent study suggests that PKM2 is redundant in a mouse model of PDAC (LSL-KrasG12D/+;Trp53flox/flox;Pdx-1-Cre (KP−/−C) mice). 60 This seems counterintuitive to the large body of evidence supporting an oncogenic role of PKM2 described above.…”

Metabolism of pancreatic cancer: paving the way to better anticancer strategies

“…Pyruvate kinase muscle isozyme 2 (PKM2) expression in pancreatic cancer cells is largely determined by nutrient conditions, and PKM2 is overexpressed under normal conditions. However, low glucose levels decrease PKM2 expression, which maintains cell survival by promoting autophagy and biomacromolecule accumulation and reducing oxidative stress [64].…”

Expression of Genes Involved in Glycolytic Pathway Upon Glucose Limitation in Leukemia Cells

“…In glioblastoma cell lines, a decrease in PKM2 mRNA expression was observed by suppression of GLUT3 with siRNA 14 . In a study with pancreatic cancer cells, the inhibition of PKM2 expression in the normal glucose medium did not affect cell growth and proliferation, whereas the suppression of PKM2 expression in low glucose (0.5mM) medium increased cell viability 18 . In another study with lung cancer cells, it was determined that induced PKM2 mRNA expression in low glucose medium increased cell proliferation 19 .…”