title: MCL-1 dependency of cisplatin-resistant cancer cells.
abstract: The selection of human cancer cell lines in cis-diamminedichloroplatinum(II) (CDDP, best known as cisplatin) is accompanied by stereotyped alterations that contribute to the acquisition of a CDDP-resistant state. Thus, CDDP resistance often leads to the upregulation of the DNA repair enzyme poly (ADP-ribose) polymerase-1 (PARP1) with the consequent intracellular accumulation of poly (ADP-ribose) (PAR)-modified proteins. Here we report another frequent alteration accompanying CDDP resistance, namely upregulation of the antiapoptotic BCL-2 family protein MCL-1. Six out of 8 CDDP resistant cancer cell lines manifested an increase in MCL-1 protein expression level, while only a minority of cell lines overexpressed BCL-2 or BCL-XL. BCL-XL was decreased in six out of 8 cancer cell lines. Importantly, MCL-1 overexpressing, CDDP resistant cells appear to be 'addicted' to MCL-1 because they died upon depletion of MCL-1 by RNA interference or pharmacological inhibition of MCL-1 expression by the BH3 mimetic obatoclax. Knockdown of PARP1 did not succeed in reducing MCL-1 expression, while depletion or inhibition of MCL-1 failed to affect the activity of PARP1. Hence, the two resistance mechanisms are not linked to each other by a direct cause-effect relationship. Importantly, CDDP-resistant, MCL-1 overexpressing human non-small cell lung cancers responded to monotherapy with obatoclax in vivo, in xenotransplanted mice, underscoring the probable therapeutic relevance of these findings.
authors.affiliation: Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, INSERM U1138, F-75006 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, F-75005 Paris, France; Metabolomics and Cell Biology Platforms, Gustave Roussy, F-94805 Villejuif, France.
authors.forename: Judith
authors.initials: J
authors.lastname: Michels
authors.affiliation: Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, INSERM U1138, F-75006 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, F-75005 Paris, France; Metabolomics and Cell Biology Platforms, Gustave Roussy, F-94805 Villejuif, France; Université Paris Sud, F-94805 Villejuif, France.
authors.forename: Florine
authors.initials: F
authors.lastname: Obrist
authors.affiliation: Regina Elena National Cancer Institute, 00144 Rome, Italy.
authors.forename: Ilio
authors.initials: I
authors.lastname: Vitale
authors.affiliation: Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, INSERM U1138, F-75006 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, F-75005 Paris, France; Metabolomics and Cell Biology Platforms, Gustave Roussy, F-94805 Villejuif, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Lissa
authors.affiliation: Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, INSERM U1138, F-75006 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, F-75005 Paris, France; Metabolomics and Cell Biology Platforms, Gustave Roussy, F-94805 Villejuif, France.
authors.forename: Pauline
authors.initials: P
authors.lastname: Garcia
authors.affiliation: Department of Medical Biosciences, Clinical Chemistry, Umeå University, Umeå SE-90187, Sweden.
authors.forename: Parviz
authors.initials: P
authors.lastname: Behnam-Motlagh
authors.affiliation: Department of Molecular Biology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu 807-8555, Japan.
authors.forename: Kimitoshi
authors.initials: K
authors.lastname: Kohno
authors.affiliation: Molecular Therapeutics Program, Karmanos Cancer Institute, Department of Oncology and Pathology, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: Gen Sheng
authors.initials: GS
authors.lastname: Wu
authors.affiliation: U769, INSERM-LabEx LERMIT, Université Paris-Sud, Faculté de Pharmacie, Châtenay Malabry F-92296, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Brenner
authors.affiliation: Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, INSERM U1138, F-75006 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, F-75005 Paris, France; Metabolomics and Cell Biology Platforms, Gustave Roussy, F-94805 Villejuif, France. Electronic address: Marie.CASTEDO-DELRIEU@gustaveroussy.fr.
authors.forename: Maria
authors.initials: M
authors.lastname: Castedo
authors.affiliation: Equipe 11 labellisée par la Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, INSERM U1138, F-75006 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, F-75005 Paris, France; Metabolomics and Cell Biology Platforms, Gustave Roussy, F-94805 Villejuif, France; Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, F-75015 Paris, France. Electronic address: kroemer@orange.fr.
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D007211:Indoles; D051379:Mice; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics / Q000378:metabolism*; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use; D034622:RNA Interference
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D011758:Pyrroles; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D002945:Cisplatin; C520962:obatoclax
keywords: Apoptosis; Chemoresistance; MCL-1; Obatoclax; PARP1