Protein Kinase C delta Supports Survival of MDA-MB-231 Breast Cancer Cells by Suppressing the ERK1/2 Pathway
(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)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/1518343
- author
- Kalstad Lönne, Gry LU ; Masoumi, Katarzyna LU ; Lennartsson, Johan and Larsson, Christer LU
- organization
- publishing date
- 2009
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Journal of Biological Chemistry
- volume
- 284
- issue
- 48
- pages
- 33456 - 33465
- publisher
- American Society for Biochemistry and Molecular Biology
- external identifiers
-
- wos:000272028500052
- scopus:70450263302
- pmid:19833733
- pmid:19833733
- ISSN
- 1083-351X
- DOI
- 10.1074/jbc.M109.036186
- language
- English
- LU publication?
- yes
- additional info
- 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)
- id
- 3f4f093e-0502-4f42-bd10-0b665f746b3a (old id 1518343)
- date added to LUP
- 2016-04-01 12:22:29
- date last changed
- 2022-02-26 06:16:52
@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 = {{American Society for Biochemistry and Molecular Biology}},
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}},
doi = {{10.1074/jbc.M109.036186}},
volume = {{284}},
year = {{2009}},
}