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.
Highlights
BRAF is one of the top12 mutant genes in human malignancies, with the substitution at position 600 from a valine to a glutamic acid (BRAF-V600E) the most common [1, 2]
It is worth noting that this regulation is conserved in human malignancies, since the two proteins are significantly co-expressed in human CRCs, representing a potential therapeutic window for tumor-selective targeting of BRAFdriven colorectal malignancies [12]. Based on this well-characterized TRAP1 cyto protective network and the knowledge that the RASRAF-ERK axis drives extracellular survival stimuli to mitochondria [4], we evaluated the relationship between TRAP1 regulation of MTP and BRAF signaling in mitochondria, with this study reporting that TRAP1 is a downstream effector of the BRAF cytoprotective pathway
In order to explore further whether BRAF antiapoptotic response involves inhibition of the mitochondrial apoptotic pathway, l-OHPinduced mitochondrial depolarization was evaluated in BRAF-wt COLO320 in comparison to BRAFV600E HT29 cells (Figure 2A), and in COLO320 cells transfected with BRAF-wt or BRAF-V600E constructs (Figure 2B)
Summary
BRAF is one of the top mutant genes in human malignancies, with the substitution at position 600 from a valine to a glutamic acid (BRAF-V600E) the most common [1, 2]. The oncogenic activation of BRAF drives the inappropriate activation of ERK signaling and the deregulation of cell proliferation [5], and is responsible for the inhibition of the mitochondrial apoptotic pathway [6,7,8], the latter being consistent with the apoptosis-resistant phenotype of BRAF-driven cancer cells. In this perspective, BRAF translocation to mitochondria represents a prerequisite for enabling resistance to apoptosis and this results in inhibition of cytochrome c release and inactivation of the caspase cascade [7], the molecular mechanisms of BRAF antiapoptotic responses in mitochondria are not fully elucidated. The molecular characterization of BRAF-dependent antiapoptotic mechanisms is the prerequisite for targeting the BRAF survival pathway, representing a major clinical need, based on the lack of appropriate and effective treatments for these tumors [11]
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