title: Increased expression of VDAC1 sensitizes carcinoma cells to apoptosis induced by DNA cross-linking agents.
abstract: A major clinical problem regarding antitumoral treatment with DNA cross-linking agents such as cisplatin (Cisp), mechlorethamine (HN2) or its derivative melphalan (MLP) is intrinsic or acquired resistance to therapy, which frequently results from a resistance to apoptosis induction. In this study, aimed to identify novel sensitizing targets to DNA cross-linker-induced cell death, we demonstrated that MLP, Cisp and HN2 induce mitochondrial permeability transition pore (PTP)-mediated apoptosis in cervical and colon carcinoma cells. This apoptotic pathway is characterized by dissipation of the mitochondrial membrane potential, production of ROS, mitochondrial translocation of Bax, release of apoptogenic factors, caspase activation and nuclear alterations. The opening of PTP and subsequent apoptosis was reduced in Bax deficient cells and in cells with elevated Bcl-2 level, but not in cells invalidated for Bak. We further showed that, among the pro-apoptotic PTP regulators tested (VDAC1, creatine kinase, ANT1 and ANT3), exogenous overexpression of VDAC1 was the most effective in enhancing Cisp- and MLP-induced apoptosis. In addition, pharmacologically induced up-regulation of VDAC1 by the chemotherapeutic agent arsenic trioxide (As(2)O(3)) greatly sensitized HeLa cells to Cisp and MLP treatment. These data indicate that increased expression of VDAC1 appears as a promising strategy to improve DNA cross-linker-induced chemotherapy.
authors.affiliation: INSERM UMR-S 769, LabEx LERMIT, Université Paris-Sud 11, 5 rue J B Clement, Chatenay-Malabry, France. sharaf_os@hotmail.com
authors.forename: Ossama
authors.initials: O
authors.lastname: Sharaf el dein
authors.forename: Cindy
authors.initials: C
authors.lastname: Gallerne
authors.forename: Catherine
authors.initials: C
authors.lastname: Brenner
authors.forename: Christophe
authors.initials: C
authors.lastname: Lemaire
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D003432:Cross-Linking Reagents / Q000737:chemistry / Q000494:pharmacology*; D004247:DNA / Q000737:chemistry; D005260:Female; D006367:HeLa Cells; D006801:Humans; D008466:Mechlorethamine / Q000494:pharmacology; D008558:Melphalan / Q000494:pharmacology; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D050995:Voltage-Dependent Anion Channel 1 / Q000235:genetics / Q000378:metabolism*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C494772:BAK1 protein, human; C494826:BAX protein, human; D003432:Cross-Linking Reagents; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D019253:Proto-Oncogene Proteins c-bcl-2; C494762:VDAC1 protein, human; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D008466:Mechlorethamine; D004247:DNA; D050995:Voltage-Dependent Anion Channel 1; D002945:Cisplatin; D008558:Melphalan