Reversing the Paradigm: Protein Kinase C as a Tumor Suppressor

Trends Pharmacol Sci. 2017 May;38(5):438-447. doi: 10.1016/j.tips.2017.02.002. Epub 2017 Mar 8.

Abstract

The discovery in the 1980s that protein kinase C (PKC) is a receptor for the tumor-promoting phorbol esters fueled the dogma that PKC is an oncoprotein. Yet 30+ years of clinical trials for cancer using PKC inhibitors not only failed, but in some instances worsened patient outcome. The recent analysis of cancer-associated mutations, from diverse cancers and throughout the PKC family, revealed that PKC isozymes are generally inactivated in cancer, supporting a tumor suppressive function. In keeping with a bona fide tumor suppressive role, germline causal loss-of-function (LOF) mutations in one isozyme have recently been identified in lymphoproliferative disorders. Thus, strategies in cancer treatment should focus on restoring rather than inhibiting PKC.

Keywords: LOF; PKC; diacylglycerol; phorbol esters; tumor suppressor.

Publication types

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

MeSH terms

  • Animals
  • Genes, Tumor Suppressor
  • Germ-Line Mutation
  • Humans
  • Neoplasms / enzymology*
  • Neoplasms / genetics*
  • Protein Kinase C / genetics*
  • Protein Kinase C / metabolism*

Substances

  • Protein Kinase C