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

Abstract

Mechanisms that mediate apoptosis resistance are attractive therapeutic targets for cancer. Protein kinase C␦ (PKC␦) 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␦ 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␦-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␦ 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␦ down-regulation. However, PKC␦ silencing also induced increased MEK1/2 phosphorylation, indicating that PKC␦ regulates ERK1/2 phosphorylation both upstream and downstream. Moreover, PKC␦ 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␦ as a potential target for therapy of breast cancers with high activity of the ERK1/2 pathway.

PKCdelta is a positive regulator of chondrogenesis in chicken high density micromass cell cultures

“…If the observation that younger chondroblasts have the highest ERK activity in HDC is taken into consideration, it seems to be plausible to conclude that the persistently elevated ERK1/2 activity may block further differentiation of chondroblasts and in this way could be a factor involved in the complete inhibition of in vitro cartilage matrix production following PKCdelta gene silencing. However, application of gene silencing of PKCdelta had variable effects on MEK-ERK1/2 signalling pathway in different systems [39,41,42], but the majority of the investigations describes PKCdelta as a negative regulator of MEK-ERK1/2 pathway [43]. As we failed to detect any elevation in the phosphorylation of ERK1/2, instead, we found a decreasing pattern following the application of rottlerin, therefore we suppose that this compound is probably not a PKCdelta inhibitor in HDC.…”

Sphingosine Suppresses Mesothelioma Cell Proliferation by Inhibiting PKC-d and Inducing Cell Cycle Arrest at the G0/G1Phase

“…PKC-δ-induced cell proliferation in murine mammary cells is associated with activation of ERK/MAPK [22]. In contrast, PKC-δ-induced suppression of ERK1/2 is associated with the survival of MDA-MB-231 cells [33]. PKC-δ attenuates apoptosis by inducing phosphorylation and proteasomal degradation of the proapoptotic protein Bim via the MEK/MAPK pathway in immortalized and malignant keratinocytes [34].…”

Protein kinase Cα suppresses the expression of STC1 in MDA-MB-231 breast cancer cells

“…High PKCα levels were also associated with poorer survival of the patients [7]. PKCδ and PKCε are survival factors, particularly in estrogen receptor-negative breast cancer cells [8]. Furthermore, both PKCδ and PKCε contribute to resistance to a wide range of death stimuli [9,10], and PKCε expression levels in tumors have been suggested to be associated with worse outcome for breast cancer patients [11].…”

“…We have recently demonstrated that the estrogen receptor-negative MDA-MB-231 breast cancer cell line depends on PKCα for optimal growth under serum-free conditions [7] and on PKCδ for survival [8]. To gain more insight into mechanisms behind these isoform-specific functions, we down-regulated PKCα, PKCδ and PKCε specifically in this cell line and analyzed consequences on global mRNA expression.…”