@article{3bfbbd156c984d499bd9ecc124fe7b1c,
title = "S1PR3–G12-biased agonist ALESIA targets cancer metabolism and promotes glucose starvation",
abstract = "Metabolic activities are altered in cancer cells compared with those in normal cells, and the cancer-specific pathway becomes a potential therapeutic target. Higher cellular glucose consumption, which leads to lower glucose levels, is a hallmark of cancer cells. In an objective screening for chemicals that induce cell death under low-glucose conditions, we discovered a compound, denoted as ALESIA (Anticancer Ligand Enhancing Starvation-induced Apoptosis). By our shedding assay of transforming growth factor α in HEK293A cells, ALESIA was determined to act as a sphingosine-1-phosphate receptor 3–G12-biased agonist that promotes nitric oxide production and oxidative stress. The oxidative stress triggered by ALESIA resulted in the exhaustion of glucose, cellular NADPH deficiency, and then cancer cell death. Intraperitoneal administration of ALESIA improved the survival of mice with peritoneally disseminated rhabdomyosarcoma, indicating its potential as a new type of anticancer drug for glucose starvation therapy.",
keywords = "GPCR, S1PR3, biased agonist, cancer therapy, glucose starvation, nitric oxide, oxidative stress",
author = "Masayasu Toyomoto and Asuka Inoue and Kei Iida and Masatsugu Denawa and Isao Kii and {Ngako Kadji}, {Francois Marie} and Takayuki Kishi and Dohyun Im and Tatsuro Shimamura and Hiroshi Onogi and Suguru Yoshida and So Iwata and Junken Aoki and Takamitsu Hosoya and Masatoshi Hagiwara",
note = "Funding Information: We thank A. Kobayashi, M. Ajiro, M. Yamamoto, S. Ohmae, Y. Sako, E. Kanemitsu, T. Motoki, K. Motomura, T. Sawada, K. Hayashi, Y. Okuno, S. Shibata, and the M.H. laboratory members for their helpful contributions to discussions and technical assistance; K. Tomooka and K. Igawa (Kyushu University) for their help in X-ray crystal structure analysis; the Medical Research Support Center, Graduate School of Medicine, Kyoto University, for compound screening; and the Institute of Laboratory Animals and the Center for Anatomical, Pathological, and Forensic Medical Research, Graduate School of Medicine, Kyoto University, for microscopy slide preparations. We would also like to thank Editage (www.editage.jp) for English language editing. Funding: this work was supported by grants-in-aid from the Japan Agency for Medical Research and Development (AMED; grant numbers JP16lk0103007h0005, JP16bk0104034h0003, JP161m0103006j0005(c-6-2), JP18kk0305003h0003, JP18am0101092, JP18bm0804007h0002, and 19ek0109310h0002 to T.H. and M.H.; JP18gm5910013 to A.I.; JP18gm0010004 to A.I. and J.A.), AMED-CREST (Create Revolutionary Technological Seeds for Science and Technology Innovation; grant number JP16gm0510008h0006 to T.H. and M.H.), AMED-BINDS (Basis for Supporting Innovative Drug Discovery and Life Science Research; grant number JP19am0101092 to M.H. and T.H.; JP20am0101079 to S.I.), the Japanese Ministry of Education, Culture, Sports, Science, and Technology (MEXT; grant number 15H05721 to T.H. and M.H.), the Ministry of Health, Labour and Welfare of Japan (to M.H.), PRESTO from Japan Science and Technology Agency (JST; grant number JPMJPR1331 to A.I.), and Japan Society for the Promotion of Science (JSPS) KAKENHI (grant number JP19H05777 to S.I.). M.T. performed most of the cell biological experiments, in vivo studies, and analyses. M.T. and M.H. designed the project, analyzed the data, interpreted the results, and compiled the original draft of the manuscript with inputs from all authors. A.I. F.M.N.K. and T.K. performed the TGFα shedding and the NanoBiT–β-arrestin recruitment assays and analyzed the data. K.I. and M.D. performed RNA-seq and analyzed the RNA-seq data. I.K. and H.O. performed the initial experiments to identify the anticancer effects of tested compounds. D.I. performed the ligand-docking simulations. S.Y. performed the chemical syntheses, separation, and identification of compounds. T.S. S.I. J.A. and T.H. supervised and mentored other co-authors and interpreted the experimental data. All authors participated in the preparation of the manuscript. M.T. I.K. S.Y. T.H. and M.H. filed patent PCT/JP2016/063381 for ALESIA. M.T. S.Y. T.H. and M.H. filed patent PCT/JP2017/039426 for ALESIA. H.O. is a chief operating officer of KinoPharma, Inc. M.H. is a founder, shareholder, and member of the scientific advisory board of KinoPharma, Inc. and BTB Drug Development Research Center Co. Ltd, although both companies are not directly involved in ALESIA. The other authors declare that they have no competing interests. Funding Information: Funding: this work was supported by grants-in-aid from the Japan Agency for Medical Research and Development ( AMED ; grant numbers JP16lk0103007h0005 , JP16bk0104034h0003 , JP161m0103006j0005 (c-6-2), JP18kk0305003h0003 , JP18am0101092 , JP18bm0804007h0002 , and 19ek0109310h0002 to T.H. and M.H.; JP18gm5910013 to A.I.; JP18gm0010004 to A.I. and J.A.), AMED-CREST (Create Revolutionary Technological Seeds for Science and Technology Innovation; grant number JP16gm0510008h0006 to T.H. and M.H.), AMED-BINDS (Basis for Supporting Innovative Drug Discovery and Life Science Research; grant number JP19am0101092 to M.H. and T.H.; JP20am0101079 to S.I.), the Japanese Ministry of Education, Culture, Sports, Science, and Technology ( MEXT ; grant number 15H05721 to T.H. and M.H.), the Ministry of Health, Labour and Welfare of Japan (to M.H.), PRESTO from Japan Science and Technology Agency ( JST ; grant number JPMJPR1331 to A.I.), and Japan Society for the Promotion of Science ( JSPS ) KAKENHI (grant number JP19H05777 to S.I.). Publisher Copyright: {\textcopyright} 2021",
year = "2021",
month = aug,
day = "19",
doi = "10.1016/j.chembiol.2021.01.004",
language = "English",
volume = "28",
pages = "1132--1144.e9",
journal = "Cell Chemical Biology",
issn = "2451-9448",
publisher = "Elsevier Inc.",
number = "8",
}
