Inhibition of B-Raf/MEK/ERK signaling suppresses DR5 expression and impairs response of cancer cells to DR5-mediated apoptosis and T cell-induced killing

• Type of Material: Article
• Authors: Youtake Oh, Emory University; Jiusheng Deng, Emory University; Ping Yue, Emory University; Taofeek Owonikoko, Emory University; Fadlo Khuri, Emory University; Shi-Yong Sun, Emory University
• Language: English
• Date: 2016-01-28
• Publisher: Nature Publishing Group: Open Access Hybrid Model Option B
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2016 Macmillan Publishers Limited All rights reserved.
• Final Published Version (URL): http://dx.doi.org/10.1038/onc.2015.97
• Title of Journal or Parent Work: Oncogene
• ISSN: 0950-9232
• Volume: 35
• Issue: 4
• Start Page: 459
• End Page: 467
• Grant/Funding Information: This study was supported by the NIH/NCI SPORE P50 grant CA128613 (to S-Y. S. for Project 2) and Emory Winship Cancer Institute Robbins Scholar awards (to Y-T. O. and to J. D.), Melanoma Research Fund (to J. D.) and Halpern Research Scholar award (to S-Y. S.).
• Keywords: Cell Biology; Biochemistry & Molecular Biology; MELANOMA; AZD6244 ARRY-142886; Science & Technology; BRAF INHIBITORS; MEK; RECEPTOR 5 EXPRESSION; Life Sciences & Biomedicine; Oncology; MUTATIONS; SORAFENIB; Genetics & Heredity; CARCINOMA; COACTIVATION; RAF
• Research Categories: Health Sciences, General; Health Sciences, Oncology

Abstract

Inhibition of B-Raf/MEK/ERK signaling is an effective therapeutic strategy against certain types of cancers such as melanoma and thyroid cancer. While demonstrated to be effective anticancer agents, B-Raf or MEK inhibitors have also been associated with early tumor progression and development of secondary neoplasms. The ligation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) with its receptor, death receptor 5 (DR5), leading to induction of apoptosis, offers a promising anticancer strategy. Importantly, this is also a natural immunosurveillance mechanism against cancer development. We previously demonstrated that activated B-Raf/MEK/ERK signaling positively regulates DR5 expression. Hence, our current work sought to address whether B-Raf/MEK/ERK inhibition and the consequent suppression of DR5 expression impede cancer cell response to DR5 activation-induced apoptosis and activated immune cell-induced killing. We found that both B-Raf (for example, PLX4032) and MEK inhibitors (for example, AZD6244 and PD0325901) effectively inhibited ERK1/2 phosphorylation and reduced DR5 levels in both human thyroid cancer and melanoma cells. Similar to the observed effect of genetic knockdown of the B-Raf gene, pre-treatment of cancer cell lines with either B-Raf or MEK inhibitors attenuated or abolished cellular apoptotic response induced by TRAIL or the DR5 agonistic antibody AMG655 or cell killing by activated T cells. Our findings clearly show that inhibition of B-Raf/MEK/ERK signaling suppresses DR5 expression and impairs DR5 activation-induced apoptosis and T cell-mediated killing of cancer cells. These findings suggest a potential negative impact of B-Raf or MEK inhibition on TRAIL- or DR5-mediated anticancer therapy and on TRAIL/DR5-mediated immune-clearance of cancer cells.