Journal
CLINICAL CANCER RESEARCH
Volume 17, Issue 8, Pages 2216-2226Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-10-3003
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Funding
- JGW Patterson Foundation
- British Skin Foundation
- Newcastle Healthcare Charity
- Newcastle Upon Tyne Hospitals NHS Foundation Trust
- North Eastern Skin Research Fund
- Cancer Research UK in the UK
- Ministry of Health of Italy Ricerca Corrente and Ricerca Finalizzata,
- AIRC
- Fondazione Telethon in Italy
- European Commission
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Purpose: 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. Clin Cancer Res; 17(8); 2216-26. (C) 2011 AACR.
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