Protein kinase Cdelta supports survival of MDA-MB-231 breast cancer cells by suppressing the ERK1/2 pathway
2009 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 284, no 48, 33456-33465 p.Article in journal (Refereed) Published
Mechanisms that mediate apoptosis resistance are attractive therapeutic targets for cancer. Protein kinase Cdelta (PKCdelta) 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 PKCdelta 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 PKCdelta-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. PKCdelta 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 PKCdelta down-regulation. However, PKCdelta silencing also induced increased MEK1/2 phosphorylation, indicating that PKCdelta regulates ERK1/2 phosphorylation both upstream and downstream. Moreover, PKCdelta 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 PKCdelta as a potential target for therapy of breast cancers with high activity of the ERK1/2 pathway.
Place, publisher, year, edition, pages
The American Society for Biochemistry and Molecular Biology, Inc. , 2009. Vol. 284, no 48, 33456-33465 p.
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-112886DOI: 10.1074/jbc.M109.036186ISI: 000272028500052PubMedID: 19833733OAI: oai:DiVA.org:uu-112886DiVA: diva2:288707