Oncotarget

Research Papers:

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

Valentina Condelli, Francesca Maddalena, Lorenza Sisinni, Giacomo Lettini, Danilo Swann Matassa, Annamaria Piscazzi, Giuseppe Palladino, Maria Rosaria Amoroso, Franca Esposito and Matteo Landriscina _

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Oncotarget. 2015; 6:22298-22309. https://doi.org/10.18632/oncotarget.4263

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Abstract

Valentina Condelli1,*, Francesca Maddalena1,*, Lorenza Sisinni1, Giacomo Lettini1, Danilo Swann Matassa2, Annamaria Piscazzi3, Giuseppe Palladino3, Maria Rosaria Amoroso2, Franca Esposito2, Matteo Landriscina3

1Laboratory of Pre-Clinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata, Rionero in Vulture, PZ, Italy

2Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy

3Medical Oncology Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy

*These authors have contributed equally to this work

Correspondence to:

Matteo Landriscina, e-mail: matteo.landriscina@unifg.it

Franca Esposito, e-mail: franca.esposito@unina.it

Keywords: BRAF, TRAP1, apoptosis, colon cancer, drug resistance

Received: April 13, 2015     Accepted: June 01, 2015     Published: June 13, 2015

ABSTRACT

The HSP90 chaperone TRAP1 is translational regulator of BRAF synthesis/ubiquitination, since BRAF down-regulation, ERK signaling inhibition and delay of cell cycle progression occur upon TRAP1 silencing/inhibition. Since TRAP1 is upregulated in human colorectal carcinomas (CRCs) and involved in protection from apoptosis and as human BRAF-driven CRCs are poorly responsive to anticancer therapies, the relationship between TRAP1 regulation of mitochondrial apoptotic pathway and BRAF antiapoptotic signaling has been further evaluated. This study reports that BRAF cytoprotective signaling involves TRAP1-dependent inhibition of the mitochondrial apoptotic pathway. It is worth noting that BRAF and TRAP1 interact and that the activation of BRAF signaling results in enhanced TRAP1 serine-phosphorylation, a condition associated with resistance to apoptosis. Consistently, a BRAF dominant-negative mutant prevents TRAP1 serine phosphorylation and restores drug sensitivity in BRAFV600E CRC drug-resistant cells with high TRAP1 levels. In addition, TRAP1 targeting by the mitochondria-directed HSP90 chaperones inhibitor gamitrinib induces apoptosis and inhibits colony formation in BRAF-driven CRC cells. Thus, TRAP1 is a downstream effector of BRAF cytoprotective pathway in mitochondria and TRAP1 targeting may represent a novel strategy to improve the activity of proapoptotic agents in BRAF-driven CRC cells.


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