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Protein Kinase C as an Apoptosis Regulator and a Potential Prognostic Factor in Breast Cancer

Kalstad Lönne, Gry LU (2010) In Lund University, Faculty of Medicine Doctoral Dissertation Series 2010:106.
Abstract
Several protein kinase C (PKC) isoforms have been suggested as potential targets for breast cancer therapy. To explore the role for PKC isoforms in processes that facilitates malignant progression and the utility of PKC isoforms as biomarkers in breast cancer, we designed a study where we evaluated the expression of PKCα, δ, and ε in primary breast cancers as well as in breast cancer cell lines. We found that PKCα levels correlated to estrogen and progesterone receptor negativity, tumor grade, and proliferative activity, whereas PKCδ and PKCε did not correlate to clinicopathological parameters. Moreover, patients with PKCα-positive tumors showed poorer survival than patients with PKCα-negative tumors independently of other factors. We also... (More)
Several protein kinase C (PKC) isoforms have been suggested as potential targets for breast cancer therapy. To explore the role for PKC isoforms in processes that facilitates malignant progression and the utility of PKC isoforms as biomarkers in breast cancer, we designed a study where we evaluated the expression of PKCα, δ, and ε in primary breast cancers as well as in breast cancer cell lines. We found that PKCα levels correlated to estrogen and progesterone receptor negativity, tumor grade, and proliferative activity, whereas PKCδ and PKCε did not correlate to clinicopathological parameters. Moreover, patients with PKCα-positive tumors showed poorer survival than patients with PKCα-negative tumors independently of other factors. We also observed that PKCα favored proliferation and migration in cultured breast cancer cells.

Since mechanisms that mediate apoptosis resistance are attractive therapeutic targets for cancer, we also investigated the involvement of PKC isoforms in survival and apoptosis of breast cancer cells. PKCδ is considered a pro-apoptotic factor in many cell types. In breast cancer, however, it has shown both pro-survival and pro-apoptotic effects. We have found that down-regulation of PKCδ per se leads to apoptosis of MDA-MB-231 cells, a breast cancer cell lines with constitutive activation of the ERK1/2 pathway due to activation mutations of Ras and Raf. The apoptosis induced by PKCδ silencing was found to be accompanied by further increased MEK1/2 and ERK1/2 phosphorylation as well as reduced levels of the ERK1/2 phosphatase MKP3. These results suggest that PKCδ favors survival by suppressing the ERK1/2 pathway upstream and downstream of ERK1/2.

We also show that PKCδ is involved in other aspect of apoptosis regulation since it interacts with Smac in breast cancer cells. The interaction is mediated via the C1b domain in the regulatory domain of PKCδ and depends on the N-terminus of Smac. Treatment with lethal triggers, such as paclitaxel, causes dissociation of the interaction, which is accompanied with release of Smac from the mitochondria. Activation of PKC by phorbol esters rescues the interaction during paclitaxel exposure concomitant with a suppression of cell death. Taken together, we have identified a previously unrecognized interaction and suggest that the PKCδ-Smac association may prevent apoptotic effects of Smac and protect it from degradation. (Less)
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author
supervisor
opponent
  • Professor Saatcioglu, Fahri, Department of Molecular Biosciences
organization
publishing date
type
Thesis
publication status
published
subject
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
volume
2010:106
pages
112 pages
publisher
Center for Molecular Pathology, Faculty of Medicine
defense location
Patologens föreläsningssal, ingång 78, plan 2, UMAS
defense date
2010-11-19 13:00
ISSN
1652-8220
ISBN
978-91-86671-22-8
language
English
LU publication?
yes
id
d04f6efb-d92f-4296-ba3e-a4080313e7c7 (old id 1702064)
date added to LUP
2010-11-03 11:29:08
date last changed
2018-05-29 11:10:27
@phdthesis{d04f6efb-d92f-4296-ba3e-a4080313e7c7,
  abstract     = {Several protein kinase C (PKC) isoforms have been suggested as potential targets for breast cancer therapy. To explore the role for PKC isoforms in processes that facilitates malignant progression and the utility of PKC isoforms as biomarkers in breast cancer, we designed a study where we evaluated the expression of PKCα, δ, and ε in primary breast cancers as well as in breast cancer cell lines. We found that PKCα levels correlated to estrogen and progesterone receptor negativity, tumor grade, and proliferative activity, whereas PKCδ and PKCε did not correlate to clinicopathological parameters. Moreover, patients with PKCα-positive tumors showed poorer survival than patients with PKCα-negative tumors independently of other factors. We also observed that PKCα favored proliferation and migration in cultured breast cancer cells.<br/><br>
Since mechanisms that mediate apoptosis resistance are attractive therapeutic targets for cancer, we also investigated the involvement of PKC isoforms in survival and apoptosis of breast cancer cells. PKCδ is considered a pro-apoptotic factor in many cell types. In breast cancer, however, it has shown both pro-survival and pro-apoptotic effects. We have found that down-regulation of PKCδ per se leads to apoptosis of MDA-MB-231 cells, a breast cancer cell lines with constitutive activation of the ERK1/2 pathway due to activation mutations of Ras and Raf. The apoptosis induced by PKCδ silencing was found to be accompanied by further increased MEK1/2 and ERK1/2 phosphorylation as well as reduced levels of the ERK1/2 phosphatase MKP3. These results suggest that PKCδ favors survival by suppressing the ERK1/2 pathway upstream and downstream of ERK1/2.<br/><br>
We also show that PKCδ is involved in other aspect of apoptosis regulation since it interacts with Smac in breast cancer cells. The interaction is mediated via the C1b domain in the regulatory domain of PKCδ and depends on the N-terminus of Smac. Treatment with lethal triggers, such as paclitaxel, causes dissociation of the interaction, which is accompanied with release of Smac from the mitochondria. Activation of PKC by phorbol esters rescues the interaction during paclitaxel exposure concomitant with a suppression of cell death. Taken together, we have identified a previously unrecognized interaction and suggest that the PKCδ-Smac association may prevent apoptotic effects of Smac and protect it from degradation.},
  author       = {Kalstad Lönne, Gry},
  isbn         = {978-91-86671-22-8},
  issn         = {1652-8220},
  language     = {eng},
  pages        = {112},
  publisher    = {Center for Molecular Pathology, Faculty of Medicine},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {Protein Kinase C as an Apoptosis Regulator and a Potential Prognostic Factor in Breast Cancer},
  volume       = {2010:106},
  year         = {2010},
}