The p53-p66Shc Apoptotic Pathway is Dispensable for Tumor Suppression whereas the p66Shc-generated Oxidative Stress Initiates Tumorigenesis

Title:The p53-p66Shc Apoptotic Pathway is Dispensable for Tumor Suppression whereas the p66Shc-generated Oxidative Stress Initiates Tumorigenesis

Volume: 19 Issue: 15

Author(s): Elena Beltrami, Silvia Valtorta, Rosamaria Moresco, Raluca Marcu, Sara Belloli, Ambrogio Fassina, Ferruccio Fazio, Piergiuseppe Pelicci and Marco Giorgio

Affiliation:

Keywords: Mitochondria, oxidative stress, tumorigenesis, tumor suppressors

Abstract: Reactive oxygen species (ROS) are regarded as hazardous by-products of mitochondrial respiration. In addition to the respiratory chain, specific ROS-generating systems have evolved. In particular, p66Shc is a mitochondrial redox protein that oxidizes cytochrome c to generate H2O2. Consistently, the deletion of p66Shc in cells and tissue results in reduced levels of ROS and oxidative stress.

Taking advantage of the p66Shc knock out (p66KO) mouse model of decreased ROS production, we assessed the role of endogenouslyproduced ROS in tumorigenesis.

Spontaneous tumor incidence was investigated and found unaltered in two different strains, 129Sv and C57Bl/6J, p66KO mice. In addition, papilloma formation upon exposure to ultraviolet radiation (UV) or 7,12-Dimethylbenz(a)anthracene/12-O-tetradecanoylphorbol- 13-acetate (DMBA/TPA) was found to be slightly lower in the absence of p66Shc. The role of p66Shc in tumorigenesis was also investigated in the absence of the tumor suppressor gene p53 (p53KO) by generating p53-p66Shc double knock out (DKO) mice. Notably, DKO mice displayed a significantly increased lifespan compared to p53KO mice. In addition, 2-deoxy-2-(18F)fluoro-D-glucose Positron Emission Tomography ([18F]FDG PET) analysis allowed to determine that disease onset occurred later in life in DKO mice compared to p53KO and that a low percentage of these mice did not develop tumors. Overall, these results indicate that although tumor incidence is not decreased in p66KO mice, p66Shc contributes to tumor initiation, in particular upon activation by carcinogens as well as when p53- mediated tumor suppression mechanisms defect.

Cite this article as:

Beltrami Elena, Valtorta Silvia, Moresco Rosamaria, Marcu Raluca, Belloli Sara, Fassina Ambrogio, Fazio Ferruccio, Pelicci Piergiuseppe and Giorgio Marco, The p53-p66Shc Apoptotic Pathway is Dispensable for Tumor Suppression whereas the p66Shc-generated Oxidative Stress Initiates Tumorigenesis, Current Pharmaceutical Design 2013; 19 (15) . https://dx.doi.org/10.2174/1381612811319150005

DOI https://dx.doi.org/10.2174/1381612811319150005	Print ISSN 1381-6128
Publisher Name Bentham Science Publisher	Online ISSN 1873-4286