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

Kalstad Lönne, Gry LU ; Masoumi, Katarzyna LU ; Lennartsson, Johan and Larsson, Christer LU (2009) In Journal of Biological Chemistry 284(48). p.33456-33465
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... (More)
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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Biological Chemistry
volume
284
issue
48
pages
33456 - 33465
publisher
ASBMB
external identifiers
  • wos:000272028500052
  • scopus:70450263302
  • pmid:19833733
ISSN
1083-351X
DOI
10.1074/jbc.M109.036186
language
English
LU publication?
yes
id
3f4f093e-0502-4f42-bd10-0b665f746b3a (old id 1518343)
date added to LUP
2010-01-13 10:56:55
date last changed
2017-01-15 03:38:38
@article{3f4f093e-0502-4f42-bd10-0b665f746b3a,
  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.},
  author       = {Kalstad Lönne, Gry and Masoumi, Katarzyna and Lennartsson, Johan and Larsson, Christer},
  issn         = {1083-351X},
  language     = {eng},
  number       = {48},
  pages        = {33456--33465},
  publisher    = {ASBMB},
  series       = {Journal of Biological Chemistry},
  title        = {Protein Kinase C delta Supports Survival of MDA-MB-231 Breast Cancer Cells by Suppressing the ERK1/2 Pathway},
  url          = {http://dx.doi.org/10.1074/jbc.M109.036186},
  volume       = {284},
  year         = {2009},
}