Accumulation of prohibitin is a common cellular response to different stressing stimuli and protects melanoma cells from ER stress and chemotherapy-induced cell death

// Tharcisio Citrangulo Tortelli Junior 1 , Lyris Martins Franco de Godoy 2, 4, 6 , Gustavo Antonio de Souza 2, 5, 6 , Diego Bonatto 3 , Andreia Hanada Otake 1 , Renata de Freitas Saito 1 , Jose Cesar Rosa 2, 6 , Lewis Joel Greene 2, 6 and Roger Chammas 1 1 Centro de Investigacao Translacional em Oncologia (LIM24), Departamento de Radiologia e Oncologia, Faculdade de Medicina da Universidade de Sao Paulo and Instituto do Câncer do Estado de Sao Paulo, Sao Paulo, SP, Brazil 2 Departamento de Biologia Celular, Molecular e Bioagentes Patogenicos, Faculdade de Medicina de Ribeirao Preto, Universidade de Sao Paulo, Ribeirao Preto, SP, Brazil 3 Centro de Biotecnologia, Departamento de Biologia Molecular e Biotecnologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil 4 Instituto Carlos Chagas, Fiocruz Parana, PR, Brazil 5 Instituto do Cerebro, Universidade Federal do Rio Grande do Norte, Natal, RN, Brazil 6 Centro de Terapia Celular, Fundacao Hemocentro de Ribeirao Preto, Ribeirao Preto, SP, Brazil Correspondence to: Roger Chammas, email: rchammas@usp.br Lewis Joel Greene, email: ljgreene@fmrp.usp.br Keywords: melanoma, prohibitin, mitochondria, cisplatin, tunicamycin Received: December 23, 2016 Accepted: April 19, 2017 Published: May 11, 2017 ABSTRACT Melanoma is responsible for most deaths among skin cancers and conventional and palliative care chemotherapy are limited due to the development of chemoresistance. We used proteomic analysis to identify cellular responses that lead to chemoresistance of human melanoma cell lines to cisplatin. A systems approach to the proteomic data indicated the participation of specific cellular processes such as oxidative phosphorylation, mitochondrial organization and homeostasis, as well as the unfolded protein response (UPR) to be required for the survival of cells treated with cisplatin. Prohibitin (PHB) was among the proteins consistently accumulated, interacting with the functional clusters associated with resistance to cisplatin. We showed PHB accumulated at different levels in melanoma cell lines under stressing stimuli, such as (i) treatment with temozolomide (TMZ), dacarbazine (DTIC) and cisplatin; (ii) serum deprivation; (iii) tunicamycin, an UPR inducer. Prohibitin accumulated in the mitochondria of melanoma cells after cisplatin and tunicamycin treatment and its de novo accumulation led to chemoresistance melanoma cell lines. In contrast, PHB knock-down sensitized melanoma cells to cisplatin and tunicamycin treatment. We conclude that PHB participates in the survival of cells exposed to different stress stimuli, and can therefore serve as a target for the sensitization of melanoma cells to chemotherapy.