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.
Zhou
Hu
H
Institute for Biomedical Research, Xiamen University, Xiamen, Fujian 361005, China.
Liu
Wen
W
Su
Ying
Y
Wei
Zhen
Z
Liu
Jie
J
Kolluri
Siva Kumar
SK
Wu
Hua
H
Cao
Yu
Y
Chen
Jiebo
J
Wu
Yin
Y
Yan
Tingdong
T
Cao
Xihua
X
Gao
Weiwei
W
Molotkov
Andrei
A
Jiang
Fuquan
F
Li
Wen-Gang
WG
Lin
Bingzhen
B
Zhang
Hai-Ping
HP
Yu
Jinghua
J
Luo
Shi-Peng
SP
Zeng
Jin-Zhang
JZ
Duester
Gregg
G
Huang
Pei-Qiang
PQ
Zhang
Xiao-Kun
XK
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
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