title: Endothelin-1/endothelin A receptor-mediated biased signaling is a new player in modulating human ovarian cancer cell tumorigenesis.
abstract: The endothelin-1 (ET-1)/endothelin A receptor (ETAR, a G protein-coupled receptor) axis confers pleiotropic effects on both tumor cells and the tumor microenvironment, modulating chemo-resistance and other tumor-associated processes by activating Gαq- and β-arrestin-mediated pathways. While the precise mechanisms by which these effects occur remain to be elucidated, interference with ETAR signaling has emerged as a promising antitumor strategy in many cancers including ovarian cancer (OC). However, current clinical approaches using ETAR antagonists in the absence of a detailed knowledge of downstream signaling have resulted in multiple adverse side effects and limited therapeutic efficacy. To maximize the safety and efficacy of ETAR-targeted OC therapy, we investigated the role of other G protein subunits such as Gαs in the ETAR-mediated ovarian oncogenic signaling. In HEY (human metastatic OC) cells where the ET-1/ETAR axis is well-characterized, Gαs signaling inhibits ETAR-mediated OC cell migration, wound healing, proliferation and colony formation on soft agar while inducing OC cell apoptosis. Mechanistically, ET-1/ETAR is coupled to Gαs/cAMP signaling in the same ovarian carcinoma-derived cell line. Gαs/cAMP/PKA activation inhibits ETAR-mediated β-arrestin activation of angiogenic/metastatic Calcrl and Icam2 expression. Consistent with our findings, Gαs overexpression is associated with improved survival in OC patients in the analysis of the Cancer Genome Atlas data. In conclusion, our results indicate a novel function for Gαs signaling in ET-1/ETAR-mediated OC oncogenesis and may provide a rationale for a biased signaling mechanism, which selectively activates Gαs-coupled tumor suppressive pathways while blocking Gαq-/β-arrestin-mediated oncogenic pathways, to improve the targeting of the ETAR axis in OC.
authors.affiliation: Vascular Biology Center, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: Jian-peng
authors.initials: JP
authors.lastname: Teoh
authors.affiliation: Vascular Biology Center, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: Kyoung-mi
authors.initials: KM
authors.lastname: Park
authors.affiliation: Vascular Biology Center, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: Yongchao
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Vascular Biology Center, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: Qiuping
authors.initials: Q
authors.lastname: Hu
authors.affiliation: Cancer Center, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: Sangmi
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: Guangyu
authors.initials: G
authors.lastname: Wu
authors.affiliation: Cancer Center, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA; Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: Shuang
authors.initials: S
authors.lastname: Huang
authors.affiliation: Cancer Center, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: Nita
authors.initials: N
authors.lastname: Maihle
authors.affiliation: Vascular Biology Center, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA; Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA. Electronic address: ilkim@gru.edu.
authors.forename: Il-man
authors.initials: IM
authors.lastname: Kim
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D019390:Arrestins / Q000378:metabolism; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D019332:Endothelin-1 / Q000378:metabolism*; D020536:Enzyme Activators / Q000494:pharmacology; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D008954:Models, Biological; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000235:genetics; D010051:Ovarian Neoplasms / Q000098:blood supply / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D044022:Receptor, Endothelin A / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D016019:Survival Analysis; D000071557:beta-Arrestins
chemical_list: D019390:Arrestins; D019332:Endothelin-1; D020536:Enzyme Activators; D044022:Receptor, Endothelin A; D000071557:beta-Arrestins; D005576:Colforsin; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D019205:GTP-Binding Protein alpha Subunits, Gs; D000262:Adenylyl Cyclases
keywords: Biased G protein-coupled receptor signaling; Endothelin axis; Metastatic genes; β-arrestin