期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 284, 期 48, 页码 33456-33465出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M109.036186
关键词
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资金
- Swedish Cancer Society
- Swedish Research Council
- Children's Cancer Foundation of Sweden
- Malmo University Hospital Research Funds
- Kock Foundation
- Crafoord Foundation
- Ollie and Elof Ericsson Foundation
- Gunnar Nilsson Foundation
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.
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