Abstract 255: Identification of a novel TRAIL sensitizer in TRAIL-resistant cancer cells

Abstract

Abstract The Tumor Necrosis Factor Related Apoptosis Inducing Ligand (TRAIL), a TNF-family member is a highly promising agent for cancer therapy as it selectively induces apoptosis in various cancer cells but not in normal cells. However, many primary tumors are resistant to TRAIL-induced apoptosis and the resistant mechanisms are not fully understood. To identify novel TRAIL signaling regulatory molecules, we screened a siRNA library that target 719 whole human protein kinases in TRAIL-resistant lung cancer cell line (A549 cell). As a screening result, we identified a member of NIMA-related kinases as a new regulator of TRAIL-induced cell death. NEK family play key role in controlling mitosis but the role in TRAIL signaling was not elucidated. Down-regulation of NEK by siRNA dramatically increased TRAIL-induced apoptosis in TRAIL resistant cancer cells including A549 cells. However it was not effective on both etoposide and TNF/CHX-mediated apoptosis. In addition, inhibition of NEK highly activated caspase-3 in response to TRAIL. On the other hand, over-expression of NEK reduced TRAIL-induced apoptosis in TRAIL sensitive cells. Our findings suggest that NEK is a novel negative modulator of TRAIL-induced apoptosis in cancer cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 255. doi:1538-7445.AM2012-255