title: OBATOCLAX and ABT-737 induce ER stress responses in human melanoma cells that limit induction of apoptosis.
abstract: Anti-apoptotic Bcl-2 family proteins, in particular, Mcl-1, are known to play a critical role in resistance of human melanoma cells to induction of apoptosis by endoplasmic reticulum stress and other agents. The present study examined whether the BH3 mimetics, Obatoclax and ABT-737, which inhibit multiple anti-apoptotic Bcl-2 family proteins, would overcome resistance to apoptosis. We report that both agents induced a strong unfolded protein response (UPR) and that RNAi knockdown of UPR signalling proteins ATF6, IRE1α and XBP-1 inhibited Mcl-1 upregulation and increased sensitivity to the agents. These results demonstrate that inhibition of anti-apoptotic Bcl-2 proteins by Obatoclax and ABT-737 appears to elicit a protective feedback response in melanoma cells, by upregulation of Mcl-1 via induction of the UPR. We also report that Obatoclax, but not ABT-737, strongly induces autophagy, which appears to play a role in determining melanoma sensitivity to the agents.
authors.affiliation: School of Medicine and Public Health, University of Newcastle, New South Wales, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Wroblewski
authors.affiliation: School of Medicine and Public Health, University of Newcastle, New South Wales, Australia.
authors.forename: Chen Chen
authors.initials: CC
authors.lastname: Jiang
authors.affiliation: School of Medicine and Public Health, University of Newcastle, New South Wales, Australia.
authors.forename: Amanda
authors.initials: A
authors.lastname: Croft
authors.affiliation: School of Medicine and Public Health, University of Newcastle, New South Wales, Australia.
authors.forename: Margaret L
authors.initials: ML
authors.lastname: Farrelly
authors.affiliation: School of Medicine and Public Health, University of Newcastle, New South Wales, Australia.
authors.forename: Xu Dong
authors.initials: XD
authors.lastname: Zhang
authors.affiliation: Kolling Institute, Royal North Shore Hospital, University of Sydney, New South Wales, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Hersey
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects; D001713:Biphenyl Compounds / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D006801:Humans; D007211:Indoles; D008545:Melanoma / Q000473:pathology*; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics; D009596:Nitrophenols / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D011758:Pyrroles / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D056811:Unfolded Protein Response / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C501332:ABT-737; D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; D007211:Indoles; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D011758:Pyrroles; D013449:Sulfonamides; C520962:obatoclax; D002118:Calcium