Abstract
B-Raf inhibitors have been used for the treatment of some B-Raf–mutated cancers. They effectively inhibit B-Raf/MEK/ERK signaling in cancers harboring mutant B-Raf, but paradoxically activates MEK/ERK in Ras-mutated cancers. Death receptor 5 (DR5), a cell surface pro-apoptotic protein, triggers apoptosis upon ligation with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or aggregation. This study focused on determining the effects of B-Raf inhibition on DR5 expression and DR5 activation-induced apoptosis in Ras-mutant cancer cells. Using chemical and genetic approaches, we have demonstrated that the B-Raf inhibitor PLX4032 induces DR5 upregulation exclusively in Ras-mutant cancer cells; this effect is dependent on Ras/c-Raf/MEK/ERK signaling activation. PLX4032 induces DR5 expression at transcriptional levels, largely due to enhancing CHOP/Elk1-mediated DR5 transcription. Pre-exposure of Ras-mutated cancer cells to PLX4032 sensitizes them to TRAIL-induced apoptosis; this is also a c-Raf/MEK/ERK-dependent event. Collectively, our findings highlight a previously undiscovered effect of B-Raf inhibition on the induction of DR5 expression and the enhancement of DR5 activation-induced apoptosis in Ras-mutant cancer cells and hence may suggest a novel therapeutic strategy against Ras-mutated cancer cells by driving their death due to DR5-dependent apoptosis through B-Raf inhibition.
Highlights
B-Raf mutation, an oncogenic driver mutation, frequently occurs in certain types of cancers such as melanoma (50–80% of cases), papillary thyroid carcinoma (~45%), hepatocellular carcinoma (~40%) and colorectal cancer (~10%)[1,2]
PLX4032 increased the levels of both p-ERK1/2 and Death receptor 5 (DR5) in the tested cancer cell lines harboring either mutant K-Ras or N-Ras (H1299), whereas AZD6244 was still effective in suppressing ERK phosphorylation and DR5 expression (Fig. 1B)
At low concentration ranges between 50 nM and 1000 nM, dabrafenib increased p-ERK1/2 levels accompanied with elevation of DR5 in three representative Ras-mutant cell lines (Fig. 1C)
Summary
B-Raf mutation, an oncogenic driver mutation, frequently occurs in certain types of cancers such as melanoma (50–80% of cases), papillary thyroid carcinoma (~45%), hepatocellular carcinoma (~40%) and colorectal cancer (~10%)[1,2]. The most frequent mutation occurs in the kinase domain with valine being replaced by glutamic acid at codon 600 (V600E), leading to constitutive activation of B-Raf kinase and downstream MEK/ERK signaling[2] These findings have spurred the effort to develop B-Raf inhibitors as anticancer drugs. Inhibition of B-Raf or MEK in B-Raf–mutant cancer cells suppresses ERK activation accompanied by downregulation of DR5 expression and decreased cell sensitivity to DR5 activation-induced apoptosis, as we recently demonstrated[21]. We hypothesized that B-Raf inhibition in Ras-mutant cancer cells will increase DR5 expression and enhance cell response to DR5 activation-induced apoptosis due to the paradoxical activation of MEK/ERK signaling
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