Targeting TRAP1 as a downstream effector of BRAF cytoprotective pathway: A novel strategy for human BRAF-driven colorectal carcinoma

摘要: // Valentina Condelli 1, * , Francesca Maddalena Lorenza Sisinni 1 Giacomo Lettini Danilo Swann Matassa 2 Annamaria Piscazzi 3 Giuseppe Palladino Maria Rosaria Amoroso Franca Esposito Matteo Landriscina Laboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center Basilicata, Rionero in Vulture, PZ, Italy Department Molecular Medicine Medical Biotechnology, University Naples Federico II, Naples, Oncology Unit, Surgical Sciences, Foggia, These authors have contributed equally to this work Correspondence to: Landriscina, e-mail: matteo.landriscina@unifg.it Esposito, franca.esposito@unina.it Keywords: BRAF, TRAP1, apoptosis, colon cancer, drug resistance Received: April 13, 2015      Accepted: June 01, Published: 2015 ABSTRACT The HSP90 chaperone TRAP1 is translational regulator BRAF synthesis/ubiquitination, since down-regulation, ERK signaling inhibition delay cell cycle progression occur upon silencing/inhibition. Since upregulated human colorectal carcinomas (CRCs) involved protection from apoptosis as BRAF-driven CRCs are poorly responsive anticancer therapies, the relationship between regulation mitochondrial apoptotic pathway antiapoptotic has been further evaluated. This study reports that cytoprotective involves TRAP1-dependent pathway. It worth noting interact activation results enhanced serine-phosphorylation, a condition associated with apoptosis. Consistently, dominant-negative mutant prevents serine phosphorylation restores sensitivity BRAFV600E CRC drug-resistant cells high levels. In addition, targeting by mitochondria-directed chaperones inhibitor gamitrinib induces inhibits colony formation cells. Thus, downstream effector mitochondria may represent novel strategy improve activity proapoptotic agents