Paradoxical activation of MEK/ERK signaling induced by B-Raf inhibition enhances DR5 expression and DR5 activation-induced apoptosis in Ras-mutant cancer cells

• Type of Material: Article
• Authors: Youtake Oh, Emory University; Jiusheng Deng, Emory University; Ping Yue, Emory University; Shi-Yong Sun, Emory University
• Language: English
• Date: 2016-05-25
• Publisher: Nature Publishing Group
• Publication Version: Final Published Version
• Copyright Statement: © 2016, Macmillan Publishers Limited
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/srep26803
• Title of Journal or Parent Work: Scientific Reports
• ISSN: 2045-2322
• Volume: 6
• Start Page: 26803
• End Page: 26803
• Grant/Funding Information: This study was supported by Emory Winship Cancer Institute Robbins Scholar awards (to Y-T. O. and to J. D.) and Halpern Research Scholar award (to S-Y. S.). S-Y Sun is a Georgia Research Alliance Distinguished Cancer Scientist and Halpern Research Scholar.
• Keywords: DABRAFENIB; TRAMETINIB; Science & Technology; MEK INHIBITION; THERAPY; BRAF-MUTATED MELANOMA; ONCOGENIC RAS; CARCINOMA-CELLS; PROGRESSION; RECEPTOR 5 EXPRESSION; TRAIL; Multidisciplinary Sciences
• Research Categories: Health Sciences, Pharmacology; Health Sciences, Oncology

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 Rasmutant 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 TRAILinduced 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.