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

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

Risultato della ricerca: Contributo in rivistaArticolo in rivista

47 Citazioni (Scopus)

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. © 2011 American Association for Cancer Research.
Lingua originaleEnglish
pagine (da-a)2216-2226
Numero di pagine11
RivistaClinical Cancer Research
Volume17
DOI
Stato di pubblicazionePubblicato - 2011

Keywords

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols
  • Apoptosis
  • Autophagy
  • Biphenyl Compounds
  • Blotting, Western
  • Boronic Acids
  • Bortezomib
  • Cell Line, Tumor
  • Endoplasmic Reticulum
  • Female
  • Fenretinide
  • Humans
  • Luminescent Proteins
  • Melanoma
  • Mice
  • Microscopy, Fluorescence
  • Microtubule-Associated Proteins
  • Nitrophenols
  • Piperazines
  • Proto-Oncogene Proteins B-raf
  • Pyrazines
  • RNA Interference
  • Signal Transduction
  • Sulfonamides
  • Xenograft Model Antitumor Assays

Fingerprint

Entra nei temi di ricerca di 'Oncogenic B-RAF signaling in melanoma impairs the therapeutic advantage of autophagy inhibition'. Insieme formano una fingerprint unica.

Cita questo