title: The G protein-coupled receptor T-cell death-associated gene 8 (TDAG8) facilitates tumor development by serving as an extracellular pH sensor.
abstract: Tumors often are associated with a low extracellular pH, which induces a variety of cellular events. However, the mechanisms by which tumor cells recognize and react to the acidic environment have not been fully elucidated. T-cell death-associated gene 8 (TDAG8) is an extracellular pH-sensing G protein-coupled receptor that is overexpressed in various tumors and tumor cell lines. In this report, we show that TDAG8 on the surface of tumor cells facilitates tumor development by sensing the acidic environment. Overexpression of TDAG8 in mouse Lewis lung carcinoma (LLC) cells enhanced tumor development in animal models and rendered LLC cells resistant to acidic culture conditions by increasing activation of protein kinase A and extracellular signal-regulated kinase in vitro. Moreover, shRNA-mediated knockdown of endogenous TDAG8 in NCI-H460 human non-small cell lung cancer cells reduced cell survival in an acidic environment in vitro as well as tumor development in vivo. Microarray analyses of tumor-containing lung tissues of mice injected with TDAG8-expressing LLC cells revealed up-regulation of genes related to cell growth and glycolysis. These results support the hypothesis that TDAG8 enhances tumor development by promoting adaptation to the acidic environment to enhance cell survival/proliferation. TDAG8 may represent a therapeutic target for arresting tumor growth.
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Medicine, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Ihara
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Kihara
authors.forename: Fumie
authors.initials: F
authors.lastname: Hamano
authors.forename: Keisuke
authors.initials: K
authors.lastname: Yanagida
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Morishita
authors.forename: Akiko
authors.initials: A
authors.lastname: Kunita
authors.forename: Takao
authors.initials: T
authors.lastname: Yamori
authors.forename: Masashi
authors.initials: M
authors.lastname: Fukayama
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Aburatani
authors.forename: Takao
authors.initials: T
authors.lastname: Shimizu
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ishii
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D020869:Gene Expression Profiling; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D046228:Microarray Analysis; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*
chemical_list: C513334:GPR65 protein, human; C513337:GPR65 protein, mouse; D043562:Receptors, G-Protein-Coupled