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 G?q- and ?-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 G?s in the ETAR-mediated ovarian oncogenic signaling. In HEY (human metastatic OC) cells where the ET-1/ETAR axis is well-characterized, G?s 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 G?s/cAMP signaling in the same ovarian carcinoma-derived cell line. G?s/cAMP/PKA activation inhibits ETAR-mediated ?-arrestin activation of angiogenic/metastatic Calcrl and Icam2 expression. Consistent with our findings, G?s 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 G?s signaling in ET-1/ETAR-mediated OC oncogenesis and may provide a rationale for a biased signaling mechanism, which selectively activates G?s-coupled tumor suppressive pathways while blocking G?q-/?-arrestin-mediated oncogenic pathways, to improve the targeting of the ETAR axis in OC.

SUBMITTER: Teoh JP 

PROVIDER: S-EPMC4254323 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature