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, Matteo Landriscina

Research output: Contribution to journalArticlepeer-review

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 drugresistant cells with high TRAP1 levels. In addition, TRAP1 targeting by the mitochondriadirected 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.

Original languageEnglish
Pages (from-to)22298-22309
Number of pages12
JournalOncotarget
Volume6
Issue number26
Publication statusPublished - 2015

Keywords

  • Apoptosis
  • BRAF
  • Colon cancer
  • Drug resistance
  • TRAP1

ASJC Scopus subject areas

  • Oncology

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