Control of Nutrient Stress-Induced Metabolic Reprogramming by PKC

Tumor cells have high-energetic and anabolic needs and are known to adapt their metabolism to be able to survive and keep proliferating under conditions of nutrient stress. We show that PKC

ζ

deficiency promotes the plasticity necessary for cancer cells to reprogram their metabolism to utilize glutamine through the serine biosynthetic pathway in the absence of glucose. PKC

ζ

represses the expression of two key enzymes of the pathway, PHGDH and PSAT1, and phosphorylates PHGDH at key residues to inhibit its enzymatic activity. Interestingly, the loss of PKC

ζ

in mice results in enhanced intestinal tumorigenesis and increased levels of these two metabolic enzymes, whereas patients with low levels of PKC

ζ

have a poor prognosis. Furthermore, PKC

ζ

and caspase-3 activities are correlated with PHGDH levels in human intestinal tumors. Taken together, this demonstrates that PKC

ζ

is a critical metabolic tumor suppressor in mouse and human cancer.

º PKC

ζ

loss allows cancer cells to proliferate under glucose-deprived conditions
º PKC

ζ

controls metabolic reprogramming in cancer cells under nutrient stress
º PKC

ζ

loss promotes glutamine utilization through the serine biosynthetic pathway
º PKC

ζ

acts as a metabolic tumor suppressor by inhibiting PHGDH expression and activity

Cancer cells reprogram metabolic pathways to fuel their energetic demands. PKC

ζ

is found to be an important metabolic tumor suppressor that prevents the activation of key enzymes involved in metabolic reprogramming and cancer progression in mice and humans.

Cell , résumé, 2012

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