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Oncogenic B-RAF signaling in melanoma impairs the therapeutic advantage of autophagy inhibition Armstrong JL; Corazzari M; Martin S; Pagliarini V; Falasca L; Hill DS; Ellis N; Al Sabah S; Redfern CP; Fimia GM; Piacentini M; Lovat PEClin Cancer Res 2011[Apr]; 17 (8): 2216-26PURPOSE: Metastatic melanoma is characterized by extremely poor survival rates and hence novel therapies are urgently required. The ability of many anticancer drugs to activate autophagy, a lysosomal-mediated catabolic process which usually promotes cell survival, suggests targeting the autophagy pathway may be a novel means to augment therapy. EXPERIMENTAL DESIGN: Autophagy and apoptosis were assessed in vitro in human melanoma cell lines in response to clinically achievable concentrations of the endoplasmic reticulum (ER) stress-inducing drugs fenretinide or bortezomib, and in vivo using a s.c. xenograft model. RESULTS: Autophagy was activated in response to fenretinide or bortezomib in B-RAF wild-type cells, shown by increased conversion of LC3 to the autophagic vesicle-associated form (LC3-II) and redistribution to autophagosomes and autolysosomes, increased acidic vesicular organelle formation and autophagic vacuolization. In contrast, autophagy was significantly reduced in B-RAF-mutated melanoma cells, an effect attributed partly to oncogenic B-RAF. Rapamycin treatment was unable to stimulate LC3-II accumulation or redistribution in the presence of mutated B-RAF, indicative of de-regulated mTORC1-dependent autophagy. Knockdown of Beclin-1 or ATG7 sensitized B-RAF wild-type cells to fenretinide- or bortezomib-induced cell death, demonstrating a pro-survival function of autophagy. In addition, autophagy was partially reactivated in B-RAF-mutated cells treated with the BH3 mimetic ABT737 in combination with fenretinide or bortezomib, suggesting autophagy resistance is partly mediated by abrogated Beclin-1 function. CONCLUSIONS: Our findings suggest inhibition of autophagy in combination with ER stress-inducing agents may represent a means by which to harness autophagy for the therapeutic benefit of B-RAF wild-type melanoma.|Animals[MESH]|Antineoplastic Combined Chemotherapy Protocols/*therapeutic use[MESH]|Apoptosis/drug effects[MESH]|Autophagy/*drug effects[MESH]|Biphenyl Compounds/administration & dosage/pharmacology[MESH]|Blotting, Western[MESH]|Boronic Acids/administration & dosage/pharmacology[MESH]|Bortezomib[MESH]|Cell Line, Tumor[MESH]|Endoplasmic Reticulum/metabolism[MESH]|Female[MESH]|Fenretinide/administration & dosage/pharmacology[MESH]|Humans[MESH]|Luminescent Proteins/genetics/metabolism[MESH]|Melanoma/*drug therapy/metabolism/pathology[MESH]|Mice[MESH]|Microscopy, Fluorescence[MESH]|Microtubule-Associated Proteins/genetics/metabolism[MESH]|Nitrophenols/administration & dosage/pharmacology[MESH]|Piperazines/administration & dosage/pharmacology[MESH]|Proto-Oncogene Proteins B-raf/genetics/*metabolism[MESH]|Pyrazines/administration & dosage/pharmacology[MESH]|RNA Interference[MESH]|Signal Transduction/*drug effects[MESH]|Sulfonamides/administration & dosage/pharmacology[MESH]|Xenograft Model Antitumor Assays[MESH] |
