Protein Kinase C delta Supports Survival of MDA-MB-231 Breast Cancer Cells by Suppressing the ERK1/2 Pathway

Gry Kalstad Lönne, Katarzyna Masoumi, Johan Lennartsson, Christer Larsson

Research output: Contribution to journalArticlepeer-review

37 Citations (SciVal)

Abstract

Mechanisms that mediate apoptosis resistance are attractive therapeutic targets for cancer. Protein kinase C delta (PKC delta) is considered a pro-apoptotic factor in many cell types. In breast cancer, however, it has shown both pro-survival and pro-apoptotic effects. Here, we report for the first time that down-regulation of PKC delta per se leads to apoptosis of MDA-MB-231 cells. Inhibition of MEK1/2 by either PD98059 or U0126 suppressed the induction of apoptosis of PKC delta-depleted MDA-MB-231 cells but did not support survival of MCF-7 or MDA-MB-468 cells. Basal ERK1/2 phosphorylation was substantially higher in MDA-MB-231 cells than in the other cell lines. PKC delta depletion led to even higher ERK1/2 phosphorylation levels and also to lower expression levels of the ERK1/2 phosphatase MKP3. Depletion of MKP3 led to apoptosis and higher levels of ERK1/2 phosphorylation, suggesting that this may be a mechanism mediating the effect of PKC delta down-regulation. However, PKC delta silencing also induced increased MEK1/2 phosphorylation, indicating that PKC delta regulates ERK1/2 phosphorylation both upstream and downstream. Moreover, PKC delta silencing led to increased levels of the E3 ubiquitin ligase Nedd4, which is a potential regulator of MKP3, because down-regulation led to increased MKP3 levels. Our results highlight PKC delta as a potential target for therapy of breast cancers with high activity of the ERK1/2 pathway.
Original languageEnglish
Pages (from-to)33456-33465
JournalJournal of Biological Chemistry
Volume284
Issue number48
DOIs
Publication statusPublished - 2009

Bibliographical note

The information about affiliations in this record was updated in December 2015.
The record was previously connected to the following departments: Tumour Cell Biology (013017530)

Subject classification (UKÄ)

  • Cancer and Oncology

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