NSAID sulindac and its analog bind RXRalpha and inhibit RXRalpha-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-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.
Mesh Terms:
Animals, Anti-Inflammatory Agents, Non-Steroidal, Apoptosis, Cell Line, Cell Line, Tumor, Cell Proliferation, Cell Survival, Cytoplasm, Dinoprostone, Drug Design, Humans, Mice, Mice, Inbred BALB C, Mice, Nude, Models, Molecular, Neoplasms, Phosphatidylinositol 3-Kinases, Prostaglandin-Endoperoxide Synthases, Protein Binding, Protein Processing, Post-Translational, Proto-Oncogene Proteins c-akt, Retinoid X Receptor alpha, Sequence Deletion, Signal Transduction, Sulindac, Transcriptional Activation, Transfection, Tretinoin, Tumor Necrosis Factor-alpha, Xenograft Model Antitumor Assays, bcl-2-Associated X Protein
Animals, Anti-Inflammatory Agents, Non-Steroidal, Apoptosis, Cell Line, Cell Line, Tumor, Cell Proliferation, Cell Survival, Cytoplasm, Dinoprostone, Drug Design, Humans, Mice, Mice, Inbred BALB C, Mice, Nude, Models, Molecular, Neoplasms, Phosphatidylinositol 3-Kinases, Prostaglandin-Endoperoxide Synthases, Protein Binding, Protein Processing, Post-Translational, Proto-Oncogene Proteins c-akt, Retinoid X Receptor alpha, Sequence Deletion, Signal Transduction, Sulindac, Transcriptional Activation, Transfection, Tretinoin, Tumor Necrosis Factor-alpha, Xenograft Model Antitumor Assays, bcl-2-Associated X Protein
Cancer Cell
Date: Jun. 15, 2010
PubMed ID: 20541701
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