NSAID sulindac and its analog bind RXRalpha and inhibit RXRalpha-dependent AKT signaling

  • Cancer Cell. 2010 Jun 15;17(6):560-73. doi: 10.1016/j.ccr.2010.04.023.
Hu Zhou  1 ,  Wen Liu ,  Ying Su ,  Zhen Wei ,  Jie Liu ,  Siva Kumar Kolluri ,  Hua Wu ,  Yu Cao ,  Jiebo Chen ,  Yin Wu ,  Tingdong Yan ,  Xihua Cao ,  Weiwei Gao ,  Andrei Molotkov ,  Fuquan Jiang ,  Wen-Gang Li ,  Bingzhen Lin ,  Hai-Ping Zhang ,  Jinghua Yu ,  Shi-Peng Luo ,  Jin-Zhang Zeng ,  Gregg Duester ,  Pei-Qiang Huang ,  Xiao-Kun Zhang
Affiliations
  • 1. Institute for Biomedical Research, Xiamen University, Xiamen, Fujian 361005, China.
PMID: 20541701 DOI: 10.1016/j.ccr.2010.04.023
Abstract

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 (RXRalpha). We identified an N-terminally truncated RXRalpha (tRXRalpha) in several Cancer cell lines and primary tumors, which interacted with the p85alpha subunit of phosphatidylinositol-3-OH kinase (PI3K). Tumor necrosis factor-alpha (TNFalpha) promoted tRXRalpha interaction with the p85alpha, activating PI3K/Akt signaling. When combined with TNFalpha, Sulindac inhibited TNFalpha-induced tRXRalpha/p85alpha 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 RXRalpha but lacks COX inhibitory activity. K-80003 displayed enhanced efficacy in inhibiting tRXRalpha-dependent Akt activation and tRXRalpha tumor growth in Animals.

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