title: Evidence for aldosterone-dependent growth of renal cell carcinoma.
abstract: The aim if this study was to investigate the hypothesis that K-RAS 4A is upregulated in a mineralocorticoid-dependent manner in renal cell carcinoma and that this supports the proliferation and survival of some renal cancers. Expression of the K-RAS in renal tumour tissues and cell lines was examined by real-time PCR and Western blot and mineralocorticoid receptor, and its gatekeeper enzyme 11β-hydroxysteroid dehydrogenase-2 was examined by immunocytochemistry on a tissue microarray of 27 cases of renal cell carcinoma. Renal cancer cells lines 04A018 (RCC4 plus VHL) and 04A019 (RCC4 plus vector alone) were examined for the expression of K-RAS4A and for the effect on K-RAS expression of spironolactone blockade of the mineralocorticoid receptor. K-RAS4A was suppressed by siRNA, and the effect on cell survival, proliferation and activation of the Akt and Raf signalling pathways was investigated in vitro. K-RAS4A was expressed in RCC tissue and in the renal cancer cell lines but K-RAS was downregulated by spironolactone and upregulated by aldosterone. Spironolactone treatment and K-RAS suppression both led to a reduction in cell number in vitro. Both Akt and Raf pathways showed activation which was dependent on K-RAS expression. K-RAS expression in renal cell carcinoma is at least partially induced by aldosterone. Aldosterone supports the survival and proliferation of RCC cells by upregulation of K-RAS acting through the Akt and Raf pathways.
authors.affiliation: Division of Cancer Research, Medical Research Institute, University of Dundee, Ninewells Hospital and Medical School, Dundee, UK.
authors.forename: Sharon
authors.initials: S
authors.lastname: King
authors.forename: Susan
authors.initials: S
authors.lastname: Bray
authors.forename: Sarah
authors.initials: S
authors.lastname: Galbraith
authors.forename: Lesley
authors.initials: L
authors.lastname: Christie
authors.forename: Stewart
authors.initials: S
authors.lastname: Fleming
mesh_terms: D042842:11-beta-Hydroxysteroid Dehydrogenases / Q000378:metabolism; D000450:Aldosterone / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D007680:Kidney Neoplasms / Q000378:metabolism* / Q000473:pathology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D018161:Receptors, Mineralocorticoid / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013148:Spironolactone / Q000494:pharmacology; D046888:Tissue Array Analysis; D048490:raf Kinases / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D018161:Receptors, Mineralocorticoid; D013148:Spironolactone; D000450:Aldosterone; D042842:11-beta-Hydroxysteroid Dehydrogenases; D051057:Proto-Oncogene Proteins c-akt; D048490:raf Kinases; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins
keywords: K-RAS; aldosterone; mineralocorticoid receptor; renal cell carcinoma