title: NSAID sulindac and its analog bind RXRalpha and inhibit RXRalpha-dependent AKT signaling.
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.
authors.affiliation: Institute for Biomedical Research, Xiamen University, Xiamen, Fujian 361005, China.
authors.forename: Hu
authors.initials: H
authors.lastname: Zhou
authors.forename: Wen
authors.initials: W
authors.lastname: Liu
authors.forename: Ying
authors.initials: Y
authors.lastname: Su
authors.forename: Zhen
authors.initials: Z
authors.lastname: Wei
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.forename: Siva Kumar
authors.initials: SK
authors.lastname: Kolluri
authors.forename: Hua
authors.initials: H
authors.lastname: Wu
authors.forename: Yu
authors.initials: Y
authors.lastname: Cao
authors.forename: Jiebo
authors.initials: J
authors.lastname: Chen
authors.forename: Yin
authors.initials: Y
authors.lastname: Wu
authors.forename: Tingdong
authors.initials: T
authors.lastname: Yan
authors.forename: Xihua
authors.initials: X
authors.lastname: Cao
authors.forename: Weiwei
authors.initials: W
authors.lastname: Gao
authors.forename: Andrei
authors.initials: A
authors.lastname: Molotkov
authors.forename: Fuquan
authors.initials: F
authors.lastname: Jiang
authors.forename: Wen-Gang
authors.initials: WG
authors.lastname: Li
authors.forename: Bingzhen
authors.initials: B
authors.lastname: Lin
authors.forename: Hai-Ping
authors.initials: HP
authors.lastname: Zhang
authors.forename: Jinghua
authors.initials: J
authors.lastname: Yu
authors.forename: Shi-Peng
authors.initials: SP
authors.lastname: Luo
authors.forename: Jin-Zhang
authors.initials: JZ
authors.lastname: Zeng
authors.forename: Gregg
authors.initials: G
authors.lastname: Duester
authors.forename: Pei-Qiang
authors.initials: PQ
authors.lastname: Huang
authors.forename: Xiao-Kun
authors.initials: XK
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D003593:Cytoplasm / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D011499:Protein Processing, Post-Translational / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D047490:Retinoid X Receptor alpha / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013467:Sulindac / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection; D014212:Tretinoin / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D047490:Retinoid X Receptor alpha; D014409:Tumor Necrosis Factor-alpha; D051028:bcl-2-Associated X Protein; D013467:Sulindac; D014212:Tretinoin; D011451:Prostaglandin-Endoperoxide Synthases; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D015232:Dinoprostone