Format

Send to

Choose Destination
Mol Carcinog. 2017 Aug;56(8):1868-1883. doi: 10.1002/mc.22643. Epub 2017 Mar 30.

Aldosterone activates the oncogenic signals ERK1/2 and STAT3 via redox-regulated mechanisms.

Author information

1
Institute of Toxicology, Medical Faculty, University of Düsseldorf, Düsseldorf, Germany.
2
Department of Nutrition, University of California, Davis, California.
3
Department of Environmental Toxicology, University of California, Davis, California.

Abstract

Epidemiological studies found an increased risk for kidney cancer in hypertensive patients, of which a subgroup has high aldosterone (Ald) levels. We recently showed that Ald is genotoxic both in kidney tubular cells and in rats with mineralocorticoid-mediated hypertension. The present work investigated in vitro and in vivo, if the oxidative stress-mediated activation of the ERK1/2 pathway, and its downstream target STAT3, could be one mechanism involved in the potential oncogenic capability of excess Ald exposure. The effects of excess Ald were investigated in LLC-PK1 cells and in Ald-induced hypertensive rats. Ald caused cRaf, MEK1/2, and ERK1/2 phosphorylation both in LLC-PK1 cells and in rat kidneys. ERK1/2 activation led to an increased phosphorylation of MSK1, p90RSK, and STAT3. The involvement of ERK1/2 in the activation of STAT3 was evidenced by the capacity of the MEK inhibitor U0126 to prevent Ald-mediated ERK1/2 and STAT3 phosphorylation. Both in vitro and in vivo, the activation of ERK1/2 and STAT3 by Ald was dependent on the mineralocorticoid receptor and was triggered by an increase in cellular oxidants. Ald-mediated oxidant increase was in part due to the activation of the enzymes NADPH oxidase and NO synthase. Proliferation was significantly enhanced and apoptosis decreased in Ald-treated rat kidneys and/or LLC-PK1 cells. Results support the concept that the oxidant-mediated long-term activation of ERK1/2/STAT3 by persistently high Ald levels could trigger proliferative and prosurvival events. Ald-mediated promotion of cell survival and DNA damage could result in kidney cell transformation and initiation of cancer in hypertensive patients with hyperaldosteronism.

KEYWORDS:

ERK1/2; STAT3; aldosterone; kidney cancer; oxidative stress

PMID:
28272757
DOI:
10.1002/mc.22643
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for Wiley Icon for eScholarship, California Digital Library, University of California
Loading ...
Support Center