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Follicle-stimulating hormone induces lipid droplets via Gαi/o and β- arrestin in an endometrial cancer cell line

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Title: Follicle-stimulating hormone induces lipid droplets via Gαi/o and β- arrestin in an endometrial cancer cell line
Authors: Sayers, S
Anujan, P
Yu, H
Palmer, S
Nautiyal, J
Franks, S
Hanyaloglu, A
Item Type: Journal Article
Abstract: Follicle-stimulating hormone (FSH) and its G protein-coupled receptor, FSHR, represents a paradigm for receptor signaling systems that activate multiple and complex pathways. Classically, FSHR activates Gαs to increase intracellular levels of cAMP, but its ability to activate other G proteins, and β-arrestin-mediated signaling is well documented in many different cell systems. The pleiotropic signal capacity of FSHR offers a mechanism for how FSH drives multiple and dynamic downstream functions in both gonadal and non-gonadal cell types, including distinct diseases, and how signal bias may be achieved at a pharmacological and cell system-specific manner. In this study, we identify an additional mechanism of FSH-mediated signaling and downstream function in the endometrial adenocarcinoma Ishikawa cell line. While FSH did not induce increases in cAMP levels, this hormone potently activated pertussis toxin sensitive Gαi/o signaling. A selective allosteric FSHR ligand, B3, also activated Gαi/o signaling in these cells, supporting a role for receptor-mediated activation despite the low levels of FSHR mRNA. The low expression levels may attribute to the lack of Gαs/cAMP signaling as increasing FSHR expression resulted in FSH-mediated activation of the Gαs pathway. Unlike prior reports for FSH-mediated Gαs/cAMP signaling, FSH-mediated Gαi/o signaling was not affected by inhibition of dynamin-dependent receptor internalization. While chronic FSH did not alter cell viability, FSH was able to increase lipid droplet size. The β-arrestins are key adaptor proteins known to regulate FSHR signaling. Indeed, a rapid, FSH-dependent increase in interactions between β-arrestin1 and Gαi1 was observed via NanoBiT complementation in Ishikawa cells. Furthermore, both inhibition of Gαi/o signaling and siRNA knockdown of β-arrestin 1/2 significantly reduced FSH-induced lipid droplet accumulation, implying a role for a Gαi/o/β-arrestin complex in FSH functions in this cell type. As FSH/FSHR has been implicated in distinct hormone-dependent cancers, including endometrial cancer, analysis of the cancer genome database from 575 human endometrial adenocarcinoma tumors revealed that a subpopulation of samples expressed FSHR. Overall, this study highlights a novel mechanism for FSHR signal pleiotropy that may be exploited for future personalized therapeutic approaches.
Issue Date: Feb-2022
Date of Acceptance: 20-Dec-2021
URI: http://hdl.handle.net/10044/1/93691
DOI: 10.3389/fendo.2021.798866
ISSN: 1664-2392
Publisher: Frontiers Media
Start Page: 1
End Page: 15
Journal / Book Title: Frontiers in Endocrinology
Volume: 12
Copyright Statement: © 2022 Sayers, Anujan, Yu, Palmer, Nautiyal, Franks and Hanyaloglu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Sponsor/Funder: Biotechnology and Biological Sciences Research Council
Funder's Grant Number: BB/S001565/1
Keywords: FSH
G protein
Ishikawa cells
endometrial cancer
1103 Clinical Sciences
1111 Nutrition and Dietetics
Publication Status: Published
Online Publication Date: 2022-02-03
Appears in Collections:Department of Metabolism, Digestion and Reproduction
Faculty of Medicine

This item is licensed under a Creative Commons License Creative Commons