Protein kinase C ε translocation and phosphorylation by cis- diamminedichloroplatinum(II) (CDDP): Potential role in CDDP-mediated cytotoxicity

Tohru Ohmori, Carlos L. Arteaga

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

Phorbol ester-like protein kinase C (PKC) activators, such as 12-O- tetradecanoylphorbol-13-acetate, and perturbation of some growth factor receptors have been reported to alter the cytotoxicity of cisdiamminedichloroplatinum(II) (CDDP). To study the mechanism of this alteration, we have examined the effect of CDDP per se on PKC isozymes. The SKBR-3 human breast carcinoma cell line exhibits at least six different PKC isozymes (PKC α, βI, βII, δ, ε, and ζ). After exposure to 10-100 μM CDDP for 3 h, only PKC ε translocated from the plasma membrane to the nuclear membrane and to the cytosolic fraction. This translocation was observed in a time- and dose-dependent manner by Western blot and confocal microscopy. CDDP also decreased the mobility of PKC ε in the nuclear membrane fraction, an effect that was blocked by protein phosphatase 2A, suggesting drug-mediated isozyme phosphorylation. This translocation and phosphorylation were also induced by the cisplatin analogue carboplatin but not with the anticancer agents Adriamycin and Taxol. Antisense oligodeoxynucleotides against PKC ε down-regulated isozyme content, blocked drug-induced translocation, and reduced cisplatin-mediated cytotoxicity 3- fold compared to that of sense-treated cells. Antisense PKC ε also decreased SKBR-3 cell sensitivity to carboplatin but not to Adriamycin and Taxol. These data support a role for PKC ε translocation and phosphorylation on CDDP- mediated toxicity.

Original languageEnglish (US)
Pages (from-to)345-353
Number of pages9
JournalCell Growth and Differentiation
Volume9
Issue number4
StatePublished - 1998

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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