Author/Authors :
Zhou، نويسنده , , Hu and Liu، نويسنده , , Wen and Su، نويسنده , , Ying and Wei، نويسنده , , Zhen and Liu، نويسنده , , Jie and Kolluri، نويسنده , , Siva Kumar and Wu، نويسنده , , Hua-Hua Cao، نويسنده , , Yu and Chen، نويسنده , , Jiebo and Wu، نويسنده , , Yin-zhuo Yan، نويسنده , , Tingdong and Cao، نويسنده , , Xihua and Gao، نويسنده , , Weiwei and Molotkov، نويسنده , , Andrei and Jiang، نويسنده , , Fuquan and Li، نويسنده , , Wen-Gang and Lin، نويسنده , , Bingzhen and Zhang، نويسنده , , Hai-Ping and Yu، نويسنده , , Jinghua and Luo، نويسنده , , Shi-Peng and Zeng، نويسنده , , Jin-Zhang and Duester، نويسنده , , Gregg and Huang، نويسنده , , Pei-Qiang and Zhang، نويسنده , , Xiao-Kun، نويسنده ,
Abstract :
Summary
roidal 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-α (RXRα). We identified an N-terminally truncated RXRα (tRXRα) in several cancer cell lines and primary tumors, which interacted with the p85α subunit of phosphatidylinositol-3-OH kinase (PI3K). Tumor necrosis factor-α (TNFα) promoted tRXRα interaction with the p85α, activating PI3K/AKT signaling. When combined with TNFα, Sulindac inhibited TNFα-induced tRXRα/p85α 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 RXRα but lacks COX inhibitory activity. K-80003 displayed enhanced efficacy in inhibiting tRXRα-dependent AKT activation and tRXRα tumor growth in animals.
