Abstract 2625: Knockdown of death receptor 5 promotes cancer cell invasion through activation of the ERK and JNK signaling pathways.

Abstract

Abstract Death receptor 5 (DR5) is a death domain-containing transmembrane receptor and can trigger apoptosis upon overexpression or ligation with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Despite of the primary function of DR5 in induction of apoptosis, accumulating evidence suggest that DR5 may also have non-apoptotic function in regulation of cancer development and progression, which is the focus of this study. Both transient and stable knockdown of DR5 did not affect the growth of cancer cells, but significantly promoted the invasive ability of cancer cells in an in vitro matrigel invasion assay. In contrast, DR5 activation by low doses of the agonistic antibody, AMG655, suppressed cancer cell invasion. Similar results could not generated by knocking down DR4 expression. Thus, DR5 negatively regulates invasion of cancer cells. Knockdown of DR5 expression was accompanied by activation of both ERK and JNK signaling pathways as evidenced by elevate levels of p-ERK, p-JNK and p-c-Jun as well as their downstream proteins c-Jun and Fra-1. Chemical (e.g., with small molecule inhibitors) or genetic (e.g., with siRNA) inhibition of either ERK or JNK blocked DR5 knockdown-induced enhancement of cell invasion. In agreement, knockdown of c-Jun and Fra-1 had similar impact on blockage of cell invasion induced by DR5 knockdown. Hence, DR5 knockdown promotes cancer cell invasion through activation of the ERK and JNK signaling pathways and subsequent activation of AP-1. Our findings highlight a novel non-apoptotic function of DR5 as a negative regulator of cancer cell invasion and provide preliminary mechanisms to account for this function. (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, Fadlo R. Khuri, Shi-Yong Sun. Knockdown of death receptor 5 promotes cancer cell invasion through activation of the ERK and JNK signaling pathways. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2625. doi:10.1158/1538-7445.AM2013-2625