Atypical protein kinase C zeta exhibits a proapoptotic function in ovarian cancer

Mol Cancer Res. 2010 Jun;8(6):919-34. doi: 10.1158/1541-7786.MCR-09-0358. Epub 2010 May 25.

Abstract

Intracellular signaling governed by serine/threonine kinases comprises the molecular interface between cell surface receptors and the nuclear transcriptional machinery. The protein kinase C (PKC) family members are involved in the control of many signaling processes directing cell proliferation, motility, and survival. Here, we examined a role of different PKC isoenzymes in protein phosphatase 2A (PP2A) and HRSL3 tumor suppressor-dependent cell death induction in the ovarian carcinoma cell line OVCAR-3. Phosphorylation and activity of PKC isoenzymes were measured in response to PP2A or phosphoinositide 3-kinase inhibition or HRSL3 overexpression. These experiments indicated a regulation of PKC, epsilon, zeta, and iota through PP2A and/or HRSL3, but not of PKCalpha and beta. Using isoform-specific peptide inhibitors and overexpression approaches, we verified a contribution to PP2A- and HRLS3-dependent apoptosis only for PKCzeta, suggesting a proapoptotic function of this kinase. We observed a significant proportion of human ovarian carcinomas expressing high levels of PKCzeta, which correlated with poor prognosis. Primary ovarian carcinoma cells isolated from patients also responded to okadaic acid treatment with increased phosphorylation of PKCzeta and apoptosis induction. Thus, our data indicate a contribution of PKCzeta in survival control in ovarian carcinoma cells and suggest that upregulation or activation of tyrosine kinase receptors in this tumor might impinge onto apoptosis control through the negative regulation of the atypical PKCzeta.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / physiology*
  • Biomarkers, Tumor / biosynthesis
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism
  • Biomarkers, Tumor / physiology*
  • Cell Death / genetics
  • Cell Death / physiology
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cell Survival / genetics
  • Cell Survival / physiology
  • Female
  • Humans
  • Intracellular Signaling Peptides and Proteins / physiology
  • Isoenzymes / biosynthesis
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • Isoenzymes / physiology
  • Okadaic Acid / pharmacology
  • Ovarian Neoplasms / enzymology*
  • Ovarian Neoplasms / metabolism
  • Ovarian Neoplasms / pathology*
  • Phospholipases A2, Calcium-Independent
  • Phosphorylation / drug effects
  • Phosphorylation / genetics
  • Protein Kinase C / biosynthesis
  • Protein Kinase C / genetics
  • Protein Kinase C / metabolism
  • Protein Kinase C / physiology*
  • Tumor Suppressor Proteins / physiology

Substances

  • Apoptosis Regulatory Proteins
  • Biomarkers, Tumor
  • Intracellular Signaling Peptides and Proteins
  • Isoenzymes
  • Tumor Suppressor Proteins
  • Okadaic Acid
  • protein kinase C zeta
  • Protein Kinase C
  • PLA2G16 protein, human
  • Phospholipases A2, Calcium-Independent