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

SummaryNonsteroidal 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.

► NSAID Sulindac induces apoptosis by binding to RXRα
► Truncated RXRα (tRXRα) promotes PI3K/AKT signaling and cancer cell growth
► Sulindac induces TNFα-dependent apoptosis by inhibiting tRXRα/p85α interaction
► Sulindac analog lacking COX-2 activity inhibits tRXRα tumor growth in animals