Protein Kinase C delta Supports Survival of MDA-MB-231 Breast Cancer Cells by Suppressing the ERK1/2 Pathway
Författare
Summary, in English
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.
Avdelning/ar
Publiceringsår
2009
Språk
Engelska
Sidor
33456-33465
Publikation/Tidskrift/Serie
Journal of Biological Chemistry
Volym
284
Issue
48
Dokumenttyp
Artikel i tidskrift
Förlag
American Society for Biochemistry and Molecular Biology
Ämne
- Cancer and Oncology
Status
Published
ISBN/ISSN/Övrigt
- ISSN: 1083-351X