alexa The Proto-Oncoprotein c-Cbl Protects Cells against Oxidative Stress by Down-Regulating Apoptosis and is Highly Expressed in Several Cancers | OMICS International
ISSN: 1948-5956

Journal of Cancer Science & Therapy
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Research Article

The Proto-Oncoprotein c-Cbl Protects Cells against Oxidative Stress by Down-Regulating Apoptosis and is Highly Expressed in Several Cancers

Sadok Yakoub1,2, Nisrine El-Chami1,3, Krisztian Kaszas1,4, Mouhannad Malek1,5, Mohamed El Sirkasi6, Colin A. Smith3, Elias Baydoun3, Eric Tabone7, Serge N Manié1,8 and Daniel CL Régnier1*

1Cancer Research Center INSERM UMR 1052 CNRS5286, Léon Bérard Center (CLB), Lyon, France

2CNRS UMR 7054 Surgery Research Center, Medicine Faculty, Henri-Mondor Hospital, Créteil, France

3Biology Department, American University of Beirut, Beirut, Lebanon

4Assay Automation and Data/Compound, Management Innovation & Discovery, Crucell Vaccine Institute Archimedesweg 4-6, 2333 CN Leiden, Netherlands

5Inositide Laboratory-Signaling program, Babraham Institute, Babraham Research campus, Babraham, Cambridge, United Kingdom

6Laboratory Department, Higher Medical Institute, Misurata – Libya

7Laboratoire d’Anatomie et de Cytologie pathologiques, Centre Léon Bérard, Lyon, France

8University of Lyon1, F-69000 Lyon, France

*Corresponding Author:
Daniel CL Régnier
Cancer Research Center
UMR 5286 CNRS U1052 INSERM, CLB
Cheney D, 28 rue Laënnec, 69008 Lyon, France
Tel: (33)629468606, (33)474854512
Fax: (33)(0)469166660
E-mail: [email protected]

Received Date: February 16, 2014; Accepted Date: March 27, 2014; Published Date: March 31, 2014

Citation: Yakoub S, El-Chami N, Kaszas K, Malek M, El Sirkasi M, et al. (2014) The Proto-Oncoprotein c-Cbl Protects Cells against Oxidative Stress by Down-Regulating Apoptosis and is Highly Expressed in Several Cancers. J Cancer Sci Ther 6:122-135. doi: 10.4172/1948-5956.1000260

Copyright: © 2014 Yakoub S, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Objective: To determine the role of c-Cbl in the apoptotic process, using several means, stressing the role of oxidative stress in cancer cells.

Methods: Prostatic epithelial cell apopotosis of c-Cbl-/-mice were compared to wildtype mice (n: 6 per condition), upon testosterone-antagonist flutamide. c-Cbl-deficient mouse embryonic fibroblasts (MEFs) were compared to wild type MEFs under etoposide or hydrogen peroxide treatments. The use of c-Cbl RNA silencing in the human prostate adenocarcinoma cell line LNCaP allowed to reveal c-Cbl’s role in LNCaPs’ apoptosis. The role of the p38-MAPK stress pathway in the LNCAP c-Cbl anti-apoptotic effect as well as its relationship with the well-documented Grb2-associated Tyrosine-Kinase-Receptor (TKR) down-regulation were investigated, using c-Cbl and/or Grb2 RNA silencing. Human c-Cbl protein expression was analysed by Western blotting and immunostaining, comparing prostatic adenocarcinoma (x22) to benign prostatic hypertrophia (x6). In situ tissue microarrays were used to assess several human malignancies (x17 and x6 spots/tissue) and to compare the magnitude of c-Cbl and oxidative stress expression.

Results: The cellular apoptotic threshold decreased in Mouse c-Cbl-/-prostatic cells and c-Cbl-/- MEFs. Only hydrogen peroxide in c-Cbl-/-MEFs induced apoptosis up to six times more than controls. Similar results were found in LNCaPs. c-Cbl down-regulates the activation of the apoptotic ASK1-p38MAPK stress pathway. c-Cbl is overexpressed in prostate, ovary, uterus, brain, lung, colon, rectum adenocarcinoma and in rhabdomyosarcoma. We found a correlation between malignant oxidative stress and c-Cbl over-expression.

Conclusions: c-Cbl increases the cellular apoptotic threshold of wild type MEFs and mouse prostate cells. c-Cbl behaves as a strong cellular protector against oxidative stress in MEFs and LNCaPs. The p38-MAPK pathway is down-regulated by c-Cbl, possibly independently of the Grb2-associated TKR down-regulation. A high c-Cbl expression in several cancers often associated with high oxidative stress expression has been found, suggesting that c-Cbl could thereby promote their survival.

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