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

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-a (RXRa). We identified an N-terminally truncated RXRa (tRXRa) in several cancer cell lines and primary tumors, which interacted with the p85a subunit of phosphatidylinositol-3-OH kinase (PI3K). Tumor necrosis factor-a (TNFa) promoted tRXRa interaction with the p85a, activating PI3K/AKT signaling. When combined with TNFa, Sulindac inhibited TNFa-induced tRXRa/p85a 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 RXRa but lacks COX inhibitory activity. K-80003 displayed enhanced efficacy in inhibiting tRXRa-dependent AKT activation and tRXRa tumor growth in animals. a-[ordm NSAID Sulindac induces apoptosis by binding to RXRa a-[ordm Truncated RXRa (tRXRa) promotes PI3K/AKT signaling and cancer cell growth a-[ordm Sulindac induces TNFa-dependent apoptosis by inhibiting tRXRa/p85a interaction a-[ordm Sulindac analog lacking COX-2 activity inhibits tRXRa tumor growth in animals