Loss of Tumor Suppressor Gene Frees Tumor Cells from Glucose Dependence

PKC-zeta is a member of the PKC family of serine/threonine kinases, which are involved in a variety of cellular processes such as proliferation, differentiation, and secretion. Unlike the classical PKC isoenzymes which are calcium-dependent, PKC-zeta exhibits a kinase activity which is independent of calcium and diacylglycerol but not of phosphatidylserine. PKC-zeta is known to play an important role in insulin-stimulated glucose transport. Inhibition of the PKC-zeta enzyme inhibits insulin-stimulated glucose transport while its activation increases glucose transport.

The investigators reported in the January 31, 2013, issue of the journal Cell that PKC-zeta deficiency promoted the plasticity necessary for cancer cells to reprogram their metabolism to utilize glutamine through the serine biosynthetic pathway in the absence of glucose. PKC-zeta repressed the expression of two key enzymes of the pathway, PHGDH (phosphoglycerate dehydrogenase) and PSAT1 (phosphoserine aminotransferase 1), and phosphorylated PHGDH at key residues to inhibit its enzymatic activity.

The loss of PKC-zeta in mice resulted in enhanced intestinal tumorigenesis and increased levels of these two metabolic enzymes, whereas human patients with low levels of PKC-zeta had a poor prognosis. PKC-zeta and caspase-3 activities were correlated with PHGDH levels in human intestinal tumors. Taken together, these findings demonstrated that PKC-zeta was a critical metabolic tumor suppressor in mouse and human cancer.

"We found an interesting correlation in colon cancers - if a patient's tumor does not produce PKC-zeta, he has a poorer prognosis than a similar patient with the protein. We looked specifically at colon cancer in this study, but it is likely also true for other tumor types," said senior author Dr. Jorge Moscat, a professor in the tumor microenvironment program at the Sanford-Burnham Medical Institute. "If we can find an effective way to add PKC-zeta back to tumors that lack it, we would make them less suited for survival and more sensitive to current therapies."


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Sanford-Burnham Medical Institute