Oncogenic B-RAF signaling in melanoma impairs the therapeutic advantage of autophagy inhibition

Jane L. Armstrong, Marco Corazzari, Shaun Martin, Vittoria Pagliarini, Laura Falasca, David S. Hill, Nicola Ellis, Salim Al Sabah, Christopher P F Redfern, Gian Maria Fimia, Mauro Piacentini, Penny E. Lovat

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Abstract

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 lysosomalmediated 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.

Original languageEnglish
Pages (from-to)2216-2226
Number of pages11
JournalClinical Cancer Research
Volume17
Issue number8
DOIs
Publication statusPublished - Apr 15 2011

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Autophagy
Melanoma
Fenretinide
Therapeutics
Endoplasmic Reticulum Stress
Sirolimus
Heterografts
Pharmaceutical Preparations
Organelles
Cell Survival
Cell Death
Research Design
Apoptosis
Cell Line

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Armstrong, J. L., Corazzari, M., Martin, S., Pagliarini, V., Falasca, L., Hill, D. S., ... Lovat, P. E. (2011). Oncogenic B-RAF signaling in melanoma impairs the therapeutic advantage of autophagy inhibition. Clinical Cancer Research, 17(8), 2216-2226. https://doi.org/10.1158/1078-0432.CCR-10-3003

Oncogenic B-RAF signaling in melanoma impairs the therapeutic advantage of autophagy inhibition. / Armstrong, Jane L.; Corazzari, Marco; Martin, Shaun; Pagliarini, Vittoria; Falasca, Laura; Hill, David S.; Ellis, Nicola; Sabah, Salim Al; Redfern, Christopher P F; Fimia, Gian Maria; Piacentini, Mauro; Lovat, Penny E.

In: Clinical Cancer Research, Vol. 17, No. 8, 15.04.2011, p. 2216-2226.

Research output: Contribution to journalArticle

Armstrong, JL, Corazzari, M, Martin, S, Pagliarini, V, Falasca, L, Hill, DS, Ellis, N, Sabah, SA, Redfern, CPF, Fimia, GM, Piacentini, M & Lovat, PE 2011, 'Oncogenic B-RAF signaling in melanoma impairs the therapeutic advantage of autophagy inhibition', Clinical Cancer Research, vol. 17, no. 8, pp. 2216-2226. https://doi.org/10.1158/1078-0432.CCR-10-3003
Armstrong, Jane L. ; Corazzari, Marco ; Martin, Shaun ; Pagliarini, Vittoria ; Falasca, Laura ; Hill, David S. ; Ellis, Nicola ; Sabah, Salim Al ; Redfern, Christopher P F ; Fimia, Gian Maria ; Piacentini, Mauro ; Lovat, Penny E. / Oncogenic B-RAF signaling in melanoma impairs the therapeutic advantage of autophagy inhibition. In: Clinical Cancer Research. 2011 ; Vol. 17, No. 8. pp. 2216-2226.
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AU - Falasca, Laura

AU - Hill, David S.

AU - Ellis, Nicola

AU - Sabah, Salim Al

AU - Redfern, Christopher P F

AU - Fimia, Gian Maria

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