Journal
CELLULAR SIGNALLING
Volume 26, Issue 12, Pages 2885-2895Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2014.08.024
Keywords
beta-arrestin; Biased G protein-coupled receptor signaling; Endothelin axis; Metastatic genes
Categories
Funding
- American Heart Association [12GRNT12100048]
- National Institutes of Health [R01 HL124251]
- [14SDG18970040]
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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 alpha q- and beta-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 alpha s in the ETAR-mediated ovarian oncogenic signaling. In HEY (human metastatic OC) cells where the ET-1/ETAR axis is well-characterized, G alpha 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 alpha s/cAMP signaling in the same ovarian carcinoma-derived cell line. G alpha s/cAMP/PKA activation inhibits ETAR-mediated beta-arrestin activation of angiogenic/metastatic Calcrl and Icam2 expression. Consistent with our findings, G alpha 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 alpha s signaling in ET-1/ETAR-mediated OC oncogenesis and may provide a rationale for a biased signaling mechanism, which selectively activates G alpha s-coupled tumor suppressive pathways while blocking G alpha q-/beta-arrestin-mediated oncogenic pathways, to improve the targeting of the ETAR axis in OC. (C) 2014 Elsevier Inc. All rights reserved.
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