Abstract 3497: Metformin enhances TRAIL-induced apoptosis by Mcl-1 degradation via Mule in colorectal cancer cells

Abstract

Abstract Recent studies have reported that metformin is an anti-diabetic drug, and is the potential a promising anti-cancer agent. The purpose of this study is to evaluate whether metformin effectively sensitize human colorectal cancer (CRC) cells to tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. Metformin alone did not induce apoptosis, but significantly potentiated TRAIL-induced apoptosis in CRC cells. CRC cells treated with metformin and TRAIL activated the intrinsic and extrinsic pathways of caspase activation. To elucidate the underlying mechanism, we found that metformin significantly reduced the protein levels of Mcl-1 (Myeloid cell leukemia 1) in CRC cells, and overexpression of Mcl-1 attenuated the cell death by metformin alone, or in combination with TRAIL. Further experiments revealed that metformin did not affect the mRNA level, but proteasomal degradation and protein stability of Mcl-1. The metformin-induced degradation of Mcl-1 required the E3 ligase Mule, which is responsible for the polyubiquitination of Mcl-1. Taken together, our study is the first report indicating that metformin enhances TRAIL-induced apoptosis through the degradation of Mcl-1 by the proteasome machinery. Citation Format: Seong Hye Park, Dae-Hee Lee, Jung Lim Kim, Sun Il Lee, Bo Ram Kim, Yoo Jin Na, Suk Young Lee, Hong-Jun Kim, Sung Yup Joung, Sanghee Kang, Sang Cheul Oh. Metformin enhances TRAIL-induced apoptosis by Mcl-1 degradation via Mule in colorectal cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3497.