title: TAT-RasGAP317-326-mediated tumor cell death sensitization can occur independently of Bax and Bak.
abstract: The increase of cancer specificity and efficacy of anti-tumoral agents are prime strategies to overcome the deleterious side effects associated with anti-cancer treatments. We described earlier a cell-permeable protease-resistant peptide derived from the p120 RasGAP protein, called TAT-RasGAP317-326, as being an efficient tumor-specific sensitizer to apoptosis induced by genotoxins in vitro and in vivo. Bcl-2 family members regulate the intrinsic apoptotic response and as such could be targeted by TAT-RasGAP317-326. Our results indicate that the RasGAP-derived peptide increases cisplatin-induced Bax activation. We found no evidence, using in particular knock-out cells, of an involvement of other Bcl-2 family proteins in the tumor-specific sensitization activity of TAT-RasGAP317-326. The absence of Bax and Bak in mouse embryonic fibroblasts rendered them resistant to cisplatin-induced apoptosis and consequently to the sensitizing action of the RasGAP-derived peptide. Surprisingly, in the HCT116 colon carcinoma cell line, the absence of Bax and Bak did not prevent cisplatin-induced apoptosis and the ability of TAT-RasGAP317-326 to augment this response. Our study also revealed that p53, while required for an efficient genotoxin-induced apoptotic response, is dispensable for the ability of the RasGAP-derived peptide to improve the capacity of genotoxins to decrease long-term survival of cancer cells. Hence, even though genotoxin-induced Bax activity can be increased by TAT-RasGAP317-326, the sensitizing activity of the RasGAP-derived peptide can operate in the absence of a functional mitochondrial intrinsic death pathway.
authors.affiliation: Department of Physiology, University of Lausanne, Rue du Bugnon 7, 1005, Lausanne, Switzerland.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Annibaldi
authors.forename: Mathieu
authors.initials: M
authors.lastname: Heulot
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Martinou
authors.forename: Christian
authors.initials: C
authors.lastname: Widmann
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor / Q000187:drug effects; D002463:Cell Membrane Permeability; D002945:Cisplatin / Q000494:pharmacology; D020690:GTPase-Activating Proteins / Q000494:pharmacology*; D006801:Humans; D018345:Mice, Knockout; D010446:Peptide Fragments / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D020690:GTPase-Activating Proteins; D010446:Peptide Fragments; C525242:TAT-RasGAP(317-326); D016159:Tumor Suppressor Protein p53; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D002945:Cisplatin