Abstract
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 inhibitors have also been associated with increased risk of secondary neoplasms. The induction of apoptosis following ligation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) with its receptor, death receptor 5 (DR5), offers a potent anticancer strategy. Importantly, this is also a natural immunosurveillance mechanism against cancer cells. We previously demonstrated that activated B-Raf/MEK/ERK signaling positively regulates DR5 expression. Hence, our current work seeks to address whether B-Raf/MEK/ERK inhibition and the consequent suppression of DR5 expression impedes cancer cell response to DR5 activation-induced apoptosis. We found that both B-Raf (e.g., PLX4032) and MEK inhibitors (e.g., 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, pretreatment 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. Our findings clearly showed that inhibition of the B-Raf/MEK/ERK signaling suppresses DR5 expression and impairs DR5 activation-induced apoptosis. These findings warrant further investigation of potential negative impact of B-Raf or MEK inhibition on TRAIL- or DR5-targeted cancer therapy and on TRAIL/DR5-mediated cancer immunosurveillance. (This study was supported by the Georgia Cancer Coalition Distinguished Cancer Scholar award, NIH/NCI SPORE P50 grant CA128613 and Winship Cancer Institute Robbins Scholar award. FR Khuri and SY Sun are Georgia Cancer Coalition Distinguished Cancer Scholars. YT Oh is a recipient of Winship Cancer Institute Robbins Scholar award) Citation Format: You-Take Oh, Ping Yue, Taofeek K. Owonikoko, Fadlo R. Khuri, Shi-Yong Sun. Pharmacological inhibition of B-Raf/MEK/ERK signaling suppresses DR5 expression and impairs cancer cell response to DR5 activation-induced apoptosis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2288. doi:10.1158/1538-7445.AM2014-2288
Published Version
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call