title: Aldosterone mediates metastatic spread of renal cancer via the G protein-coupled estrogen receptor (GPER).
abstract: Although aldosterone is a known regulator of renal and cardiovascular function, its role as a regulator of cancer growth and spread has not been widely considered. This study tested the hypothesis that aldosterone regulates cancer cell growth/spread via G protein-coupled estrogen receptor (GPER) activation. In vitro in murine renal cortical adenocarcinoma (RENCA) cells, a widely used murine in vitro model for the study of renal cell adenocarcinoma, aldosterone increased RENCA cell proliferation to a maximum of 125 ± 3% of control at a concentration of 10 nM, an effect blocked by the GPER antagonist G15 or by GPER knockdown using short interfering (sh) RNA techniques. Further, aldosterone increased RENCA cell migration to a maximum of 170 ± 20% of control at a concentration of 100 nM, an effect also blocked by G15 or by GPER down-regulation. In vivo, after orthotopic RENCA cell renal transplantation, pulmonary tumor spread was inhibited by pharmacologic blockade of aldosterone effects with spironolactone (percentage of lung occupied by metastasis: control = 68 ± 13, spironolactone = 26 ± 8, P < 0.05) or inhibition of aldosterone synthesis with a high dietary salt diet (percentage of lung: control = 44 ± 6, high salt = 12 ± 3, P < 0.05), without reducing primary tumor size. Additionally, adrenalectomy significantly reduced the extent of pulmonary tumor spread, whereas aldosterone infusion recovered pulmonary metastatic spread toward baseline levels. Finally, inhibition of GPER either with the GPER antagonist G15 or by GPER knockdown comparably inhibited RENCA cell pulmonary metastatic cancer spread. Taken together, these findings provide strong evidence for aldosterone serving a causal role in renal cell cancer regulation via its GPER receptor; thus, antagonism of GPER represents a potential new target for treatment to reduce metastatic spread.-Feldman, R. D., Ding, Q., Hussain, Y., Limbird, L. E., Pickering, J. G., Gros, R. Aldosterone mediates metastatic spread of renal cancer via the G protein-coupled estrogen receptor (GPER).
authors.affiliation: Discipline of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, Canada; Molecular Medicine Group, Robarts Research Institute, London, Ontario, Canada; and ross.feldman@med.mun.ca.
authors.forename: Ross D
authors.initials: RD
authors.lastname: Feldman
authors.affiliation: Discipline of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, Canada; Molecular Medicine Group, Robarts Research Institute, London, Ontario, Canada; and.
authors.forename: Qingming
authors.initials: Q
authors.lastname: Ding
authors.affiliation: Molecular Medicine Group, Robarts Research Institute, London, Ontario, Canada; and.
authors.forename: Yasin
authors.initials: Y
authors.lastname: Hussain
authors.affiliation: Department of Life and Physical Sciences, Fisk University, Nashville, Tennessee, USA.
authors.forename: Lee E
authors.initials: LE
authors.lastname: Limbird
authors.affiliation: Molecular Medicine Group, Robarts Research Institute, London, Ontario, Canada; and.
authors.forename: J Geoffrey
authors.initials: JG
authors.lastname: Pickering
authors.affiliation: Molecular Medicine Group, Robarts Research Institute, London, Ontario, Canada; and.
authors.forename: Robert
authors.initials: R
authors.lastname: Gros
mesh_terms: D000450:Aldosterone / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D007680:Kidney Neoplasms / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D009362:Neoplasm Metastasis / Q000503:physiopathology*; D009374:Neoplasms, Experimental / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D013148:Spironolactone / Q000494:pharmacology
chemical_list: C532507:GPER1 protein, mouse; D000451:Mineralocorticoid Receptor Antagonists; D034741:RNA, Small Interfering; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; D013148:Spironolactone; D000450:Aldosterone
keywords: RENCA; mineralocorticoid; tumor