title: Violacein induces death of RAS-mutated metastatic melanoma by impairing autophagy process.
abstract: Treatment of metastatic melanoma still remains a challenge, since in advanced stage it is refractory to conventional treatments. Most patients with melanoma have either B-RAF or N-RAS mutations, and these oncogenes lead to activation of the RAS-RAF-MEK-ERK and AKT signal pathway, keeping active the proliferation and survival pathways in the cell. Therefore, the identification of small molecules that block metastatic cell proliferation and induce cell death is needed. Violacein, a pigment produced by Chromobacterium violaceum found in Amazon River, has been used by our group as a biotool for scrutinizing signaling pathways associated with proliferation, survival, aggressiveness, and resistance of cancer cells. In the present study, we demonstrate that violacein diminished the viability of RAS- and RAF-mutated melanoma cells (IC50value ∼500 nM), and more important, this effect was not abolished after treatment medium removal. Furthermore, violacein was able to reduce significantly the invasion capacity of metastatic melanoma cells in 3D culture. In the molecular context, we have shown for the first time that violacein causes a strong drop on histone deacetylase 6 expression, a proliferating activator, in melanoma cells. Besides, an inhibition of AXL and AKT was detected. All these molecular events propitiate an inhibition of autophagy, and consequently, melanoma cell death by apoptosis.
authors: Departamento de Ciências da Saúde, Centro Universitário Norte do Espírito Santo, Universidade Federal do Espírito Santo, São Mateus, Espírito Santo, Brazil.|Departamento de Bioquímica e Biologia Tecidual, Instituto de Biologia, Universidade Estadual de Campinas, Campinas, São Paulo, Brazil.
authors: Paola R
authors: PR
authors: Gonçalves
authors: Departamento de Bioquímica e Biologia Tecidual, Instituto de Biologia, Universidade Estadual de Campinas, Campinas, São Paulo, Brazil.
authors: Karin J P
authors: KJ
authors: Rocha-Brito
authors: Departamento de Bioquímica e Biologia Tecidual, Instituto de Biologia, Universidade Estadual de Campinas, Campinas, São Paulo, Brazil.
authors: Maruska R N
authors: MR
authors: Fernandes
authors: Departamento de Bioquímica e Biologia Tecidual, Instituto de Biologia, Universidade Estadual de Campinas, Campinas, São Paulo, Brazil.
authors: Julia L
authors: JL
authors: Abrantes
authors: Institute of Chemistry, Universidade Estadual de Campinas, Campinas, São Paulo, Brazil.|Brazilian Nanotechnology National Laboratory (LNNano-CNPEM), Campinas, SP, Brazil.
authors: Nelson
authors: N
authors: Durán
authors: Departamento de Bioquímica e Biologia Tecidual, Instituto de Biologia, Universidade Estadual de Campinas, Campinas, São Paulo, Brazil. carmenv@unicamp.br.|Unicamp. Rua Monteiro Lobato, Cidade Universitária Zeferino, 255/ Bloco E1/ Lab 01/ CEP 13083-862, Campinas, São Paulo, Brazil. carmenv@unicamp.br.
authors: Carmen V
authors: CV
authors: Ferreira-Halder
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D020558:GTP Phosphohydrolases / Q000235:genetics*; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008545:Melanoma / Q000188:drug therapy / Q000556:secondary*; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
chemical_list: D007211:Indoles; D008565:Membrane Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human; C063155:violacein
keywords: Antitumor activity; Autophagy; Melanoma; Skin carcinoma; Violacein