NSAID Sulindac and Its Analog Bind RXRalpha and Inhibit RXRalpha-dependent AKT Signaling

Overview

Journal Cancer Cell

Publisher Cell Press

Specialty Oncology

Date 2010 Jun 15

PMID 20541701

Citations 64

Authors

Hu Zhou

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

Soon will be listed here.

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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