title: BRAF V600E-dependent role of autophagy in uveal melanoma.
abstract: BACKGROUND
  Autophagy can function in a dual role in cancer development and progression: It can be cytoprotective or contribute to cell death. Therefore, determining the contextual role of autophagy between these two opposing effects is important. So far, little is known about the role of autophagy in uveal melanoma. In the present study, we looked to investigate the autophagic process, as well as its effect on cell survival in uveal melanoma cell lines under stressed conditions (starvation). The possible role of autophagy during BRAF inhibition in uveal melanoma was also sought.
  
  
  METHODS
  Two human uveal melanoma cell lines, OCM1A, which harbors the BRAF mutation V600E and Mel 290, which is BRAF wild type, were studied. Autophagy levels were determined by Western blot assay with/without the addition of autophagic flux inhibitor (bafilomycin A1). Cell proliferation was assessed by an MTT assay.
  
  
  RESULTS
  Starvation triggered autophagy in BRAF V600E-mutant OCM1A cells but not in BRAF wild-type Mel 290 cells. Enhanced autophagy helped the OCM1A cells survive under stressed conditions. The BRAF inhibitor vemurafenib upregulated autophagy through suppression of the PI3K/Akt/mTOR/p70S6 K pathway in BRAF V600E-mutant uveal melanoma cells. Autophagy inhibition impaired the treatment efficacy of vemurafenib in BRAF V600E-mutant uveal melanoma cells.
  
  
  CONCLUSIONS
  Our data demonstrate that starvation-trigged autophagy, which is BRAF V600E dependent, promotes cancer cell survival in uveal melanoma. Vemurafenib induces autophagic cell death rather than adaptive cell survival in BRAF V600E-mutant melanoma.
authors.affiliation: Department of Ophthalmology, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.|Department of Surgery, New York Presbyterian Hospital and Weill Medical College of Cornell University, New York, NY, 10021, USA.
authors.forename: Yinu
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Surgery, New York Presbyterian Hospital and Weill Medical College of Cornell University, New York, NY, 10021, USA.|Department of Surgical Oncology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.
authors.forename: Weibin
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Surgery, New York Presbyterian Hospital and Weill Medical College of Cornell University, New York, NY, 10021, USA.
authors.forename: Irene
authors.initials: I
authors.lastname: Min
authors.affiliation: Department of Surgery, New York Presbyterian Hospital and Weill Medical College of Cornell University, New York, NY, 10021, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Wyrwas
authors.affiliation: Department of Surgery, New York Presbyterian Hospital and Weill Medical College of Cornell University, New York, NY, 10021, USA.
authors.forename: Maureen
authors.initials: M
authors.lastname: Moore
authors.affiliation: Department of Surgery, New York Presbyterian Hospital and Weill Medical College of Cornell University, New York, NY, 10021, USA.
authors.forename: Rasa
authors.initials: R
authors.lastname: Zarnegar
authors.affiliation: Department of Surgery, New York Presbyterian Hospital and Weill Medical College of Cornell University, New York, NY, 10021, USA. tjfahey@med.cornell.edu.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Fahey
mesh_terms: D001343:Autophagy / Q000187:drug effects / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D007211:Indoles / Q000008:administration & dosage; D018942:Macrolides / Q000008:administration & dosage; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000008:administration & dosage; D014604:Uveal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000077484:Vemurafenib; D000098943:Uveal Melanoma
chemical_list: D007211:Indoles; D018942:Macrolides; D013449:Sulfonamides; D000077484:Vemurafenib; C040929:bafilomycin A1; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
keywords: Autophagy; BRAF inhibitor; BRAF mutation; Uveal melanoma