NSAID Sulindac and Its Analog Bind RXRα and Inhibit RXRα-Dependent AKT Signaling

作者：Zhou, Hu; Liu, Wen; Su, Ying; Wei, Zhen; Liu, Jie; Kolluri, Siva Kumar; Wu, Hua; Cao, Yu; Chen, Jiebo; Wu, Yin; Yan, Tingdong; Cao, Xihua; Gao, Weiwei; Molotkov, Andrei; Jiang, Fuquan; Li, Wen-Gang; Lin, Bingzhen; Zhang, Hai-Ping; Yu, Jinghua; Luo, Shi-Peng; Zeng, Jin-Zhang; Duester, Gregg; Huang, Pei-Qiang; Zhang, Xiao-Kun^*

来源：Cancer Cell, 2010, 17(6): 560-573.

DOI：10.1016/j.ccr.2010.04.023

• RETINOID-X-RECEPTOR
• TUMOR-NECROSIS-FACTOR
• SELECTIVE-INHIBITION
• NUCLEAR EXPORT
• EXPRESSION
• ACID
• APOPTOSIS
• CLEAVAGE
• COMPLEX
• CYCLOOXYGENASE-2

Nonsteroidal anti-inflammatory drugs (NSAIDs) exert their anticancer effects through cyclooxygenase-2 (COX-2)-dependent and independent mechanisms. Here, we report that Sulindac, an NSAID, induces apoptosis by binding to retinoid X receptor-alpha (RXR alpha). We identified an N-terminally truncated RXR alpha (tRXR alpha) in several cancer cell lines and primary tumors, which interacted with the p85 alpha subunit of phosphatidylinositol-3-OH kinase (PI3K). Tumor necrosis factor-alpha (TNF alpha) promoted tRXR alpha. interaction with the p85 alpha, activating PI3K/AKT signaling. When combined with TNF alpha, Sulindac inhibited TNF alpha-induced tRXR alpha/p85 alpha interaction, leading to activation of the death receptor-mediated apoptotic pathway. We designed and synthesized a Sulindac analog K-80003, which has increased affinity to RXR alpha but lacks COX inhibitory activity. K-80003 displayed enhanced efficacy in inhibiting tRXR alpha-dependent AKT activation and tRXR alpha tumor growth in animals.

• 出版日期2010-6-15
• 单位厦门大学