Control of nutrient stress-induced metabolic reprogramming by PKCζ in tumorigenesis

Cell. 2013 Jan 31;152(3):599-611. doi: 10.1016/j.cell.2012.12.028.


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 PKCζ 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. PKCζ 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 PKCζ in mice results in enhanced intestinal tumorigenesis and increased levels of these two metabolic enzymes, whereas patients with low levels of PKCζ have a poor prognosis. Furthermore, PKCζ and caspase-3 activities are correlated with PHGDH levels in human intestinal tumors. Taken together, this demonstrates that PKCζ is a critical metabolic tumor suppressor in mouse and human cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / metabolism*
  • Adenoma / metabolism*
  • Adenomatous Polyposis Coli Protein / genetics
  • Adenomatous Polyposis Coli Protein / metabolism
  • Animals
  • Biosynthetic Pathways
  • Cell Transformation, Neoplastic
  • Colonic Neoplasms / metabolism*
  • Glucose / metabolism
  • Humans
  • Mice
  • Protein Kinase C / metabolism*
  • Serine / biosynthesis
  • Specific Pathogen-Free Organisms
  • Stress, Physiological


  • Adenomatous Polyposis Coli Protein
  • Serine
  • protein kinase C eta
  • Protein Kinase C
  • Glucose