title: Resveratrol Overcomes Cellular Resistance to Vemurafenib Through Dephosphorylation of AKT in BRAF-mutated Melanoma Cells.
abstract: OBJECTIVE
  The serine/threonine-protein kinase B-Raf (BRAF) V600E mutant (BRAF(V600E)) inhibitor vemurafenib, has improved clinical outcomes for patients with BRAF(V600E) melanoma, but acquired cellular resistance mediated by AKT serine/threonine kinase 1 (AKT) phosphorylation limits its efficacy. We examined the effect of resveratrol on vemurafenib-resistant melanoma cells.
  
  
  METHODS
  A vemurafenib-resistant human metastatic melanoma cell line positive for the BRAF V600E mutation was established. The anti-tumorigenic effects of vemurafenib and resveratrol, both alone and in combination, were examined through analysis of cell proliferation and protein expression.
  
  
  RESULTS
  The level of phosphorylated AKT (p-AKT) was increased in the primary melanoma cells after treatment with vemurafenib, and the basal level of p-AKT was increased in vemurafenib-resistant melanoma cells. Notably, resveratrol both alone and in combination with vemurafenib effectively suppressed cell proliferation and AKT phosphorylation in both parental and vemurafenib-resistant melanoma cells.
  
  
  CONCLUSIONS
  Vemurafenib resistance can be reversed by addition of resveratrol in patients undergoing treatment with BRAF inhibitors.
authors.affiliation: Department of Cell Biology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan.
authors.forename: Hao
authors.initials: H
authors.lastname: Luo
authors.affiliation: Fukuoka General Cancer Clinic, Fukuoka, Japan.
authors.forename: Masayo
authors.initials: M
authors.lastname: Umebayashi
authors.affiliation: Department of Cell Biology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan Central Research Institute for Advanced Molecular Medicine, Fukuoka University, Fukuoka, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Doi
authors.affiliation: Fukuoka General Cancer Clinic, Fukuoka, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Morisaki
authors.affiliation: Department of Cell Biology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan Central Research Institute for Advanced Molecular Medicine, Fukuoka University, Fukuoka, Japan.
authors.forename: Senji
authors.initials: S
authors.lastname: Shirasawa
authors.affiliation: Department of Cell Biology, Faculty of Medicine, Fukuoka University, Fukuoka, Japan Central Research Institute for Advanced Molecular Medicine, Fukuoka University, Fukuoka, Japan tsunoda@fukuoka-u.ac.jp.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Tsunoda
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D008545:Melanoma / Q000188:drug therapy / Q000473:pathology; D020125:Mutation, Missense; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D000077484:Vemurafenib
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D013267:Stilbenes; D013449:Sulfonamides; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt; D000077185:Resveratrol
keywords: AKT phosphorylation; BRAF; drug resistance; melanoma; vemurafenib