Control of Nutrient Stress-Induced Metabolic Reprogramming by PKC
Menée à l'aide d'un modèle murin, cette étude met en évidence le rôle joué par la protéine kinase 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 2013