Accumulation of PHB1 is a common cellular response to different stressing stimuli and protects melanoma cells from ER stress and the cytotoxic agent cisplatin

• Grant number: 17/11408-1
• Support Opportunities: Regular Research Grants - Publications - Scientific article
• Start date: August 01, 2017
• End date: January 31, 2018
• Field of knowledge: Health Sciences - Medicine
• Principal Investigator: Roger Chammas
• Grantee: Roger Chammas
• Host Institution: Instituto do Câncer do Estado de São Paulo Octavio Frias de Oliveira (ICESP). Coordenadoria de Serviços de Saúde (CSS). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil

Abstract

Melanoma is responsible for most deaths among all skin cancers and conventionalchemotherapy fails because of the development of chemoresistance. We usedproteomic analysis to identify cellular responses that lead to the chemoresistanceof human melanoma cell lines to cisplatin. A systems approach to the proteomicdata indicated the participation of specific cellular processes such as oxidativephosphorylation, mitochondrial organization and homeostasis, as well as theunfolded protein response (UPR) to be required for the survival of cells treatedwith cisplatin. Prohibitin was among the proteins consistently accumulated,interacting with the functional clusters associated with resistance to cisplatin. Weshowed that prohibitin was accumulated under different stimuli such as (i)treatment with temozolomide and dacarbazine, as well with cisplatin (ii) serumdeprivation and (iii) tunicamycin, an unfolded protein response (UPR) inducer.Prohibitin accumulated in the mitochondria of melanoma cells after cisplatin andtunicamycin treatment and its de novo accumulation led to chemoresistancemelanoma cell lines. In contrast, prohibitin knock-down sensitized melanoma cellsto cisplatin and tunicamycin treatment. We conclude that prohibitin participatesin the survival of cells exposed to different stress stimuli, and can therefore serveas a target for the sensitization of melanoma cells to chemotherapy. (AU)