Co-inhibition of BET and proteasome enhances ER stress and Bim-dependent apoptosis with augmented cancer therapeutic efficacy. (28th October 2018)

• Record Type: Journal Article
• Authors: Qian, Guoqing; Yao, Weilong; Zhang, Shuo; Bajpai, Richa; Hall, William D.; Shanmugam, Mala; Lonial, Sagar; Sun, Shi-Yong
• Is Part Of: Cancer letters. Volume 435(2018)
• Page Start: 44
• Page End: 54
• Publication Date: 2018-10-28
• Subjects: BET -- Proteasome -- Apoptosis -- Bim -- Cancer; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2018.07.033
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: Agents that inhibit bromodomain and extra-terminal domain (BET) protein have been actively tested in the clinic as potential anticancer drugs. Proteasome inhibitors such as carfilzomib (CFZ) are FDA-approved for the treatment of patients with advanced multiple myeloma and have been tested against other cancers. The current study focuses on the combination of a BET inhibitor (e.g., JQ1) and a proteasome inhibitor (e.g., CFZ) as a novel cancer therapeutic strategy and the underlying mechanisms. The tested combination (JQ1 with CFZ) synergistically decreased cell survival and enhanced apoptosis in vitro and inhibited tumor growth in vivo . The dramatic induction of apoptosis was accompanied by enhanced elevation of Bim and ER stress. Bim knockout significantly attenuated apoptosis induced by the combination, suggesting a critical role of Bim induction in mediating the enhanced induction of apoptosis by BET and proteasome co-inhibition. The combination significantly increased Bim mRNA levels with limited effect on Bim protein stability, suggesting a primary transcriptional regulation of enhanced Bim expression. Our findings warrant further investigation of this combinatorial strategy as an effective regimen against cancer in the clinic. Highlights: The co-inhibition of BET and proteasome augments induction of apoptosis and enhances anti-tumor activity in vivo . Enhanced Bim elevation mediates the augmented induction of apoptosis by co-inhibition of BET and proteasome. Enhanced Bim elevation primarily occurs at transcriptional level and is likely secondary to augmented ER stress.