Estrogen-Induced Mitochondrial Reactive Oxygen Species as Signal-Transducing Messengers

Abstract

We report here evidence in support of the role of 17beta-estradiol- (E2-) induced mitochondrial (mt) reactive oxygen species (ROS) as signal-transducing messengers. On the basis of monitoring the oxidation of 2',7'-dichlorofluorescin by spectrofluorometry, flow cytometry, and confocal microscopy, we have identified that exposure of E2 triggers the immediate rapid production of intracellular ROS ranging from a 1- to severalfold increase in a variety of cells. E2-stimulated ROS production does not correlate with the activity of the estrogen receptor (ER) in the cells. The ROS is most likely hydrogen peroxide based on its inhibition by antioxidants and catalase and lack of any effects of E2 on O(2)(*)(-) or NO(*) formation. Confocal microscopy showed that ROS is localized in the perinuclear mitochondria. E2 through anchorage- and integrin-dependent signaling to mitochondria increased ROS generation. Increased intracellular ROS formation identified here for the first time may explain the mechanism of previously reported oxidative damage and subsequent genetic alterations including mutations produced by elevated concentrations of estrogens. The functional consequences of E2-induced ROS formation included the enhanced cell motility as shown by the increase in cdc42 and activation of Pyk2 and the increased phosphorylation of signaling proteins c-jun and CREB. E2-induced ROS activated the binding of three oxidant-sensitive transcription factors: AP-1, CREB, and nuclear respiratory factor 1. In addition to ERs as signaling molecules, our findings further revealed that E2-induced mt ROS also act as signal transducing messengers and suggest new targets for the development of antioxidant-based drugs or antioxidant gene therapy for the prevention and treatment of estrogen-dependent cancer.

RETRACTED ARTICLE: Regulation of estrogen receptor signaling in breast carcinogenesis and breast cancer therapy

“…Physiological concentrations of E2 stimulate a rapid production of intracellular ROS through the mitochondrial respiration chain in epithelial cells. E2-induced ROS production does not depend on the presence of ER on breast cancer cells as ERnegative cell lines such as MDA-MB 468 can produce ROS equal to or more than that of ERα-positive MCF7, T47D, and ZR75 cell lines [102]. ROS reversibly regulates cysteinebased phosphatases, which include protein tyrosine phosphatases (PTPs), dual-spec-ificity phosphatases (such as, Cdc25s), low molecular weight PTPs, and the lipid phosphatase PTEN.…”

Overexpression of peroxiredoxin-3 and -5 is a potential biomarker for prognosis in endometrial cancer

“…Felty et al (21) suggested that physiological estrogen concentrations could induce significant oxidative stress in vitro and that estrogen-induced ROS formation occurs in the mitochondria. For example, in estrogen receptor (ER)-positive breast cancer, which is a major estrogen-dependent cancer, estrogens are important cellular ROS inducers (22).…”

In vitro electrical-stimulated wound-healing chip for studying electric field-assisted wound-healing process

“…69 EF induced the generation of O 2 À via the activation of NADPH oxidase and then activated the MAPKs, PI3Ks, and ERK pathways which were related to the rearrangement of cytoskeleton and directional migration of cells. As suggested by other research groups, low concentration of ROS promoted cell-to-cell communication and cell proliferation, 70 while high concentration of ROS induced oxidative damage to cells and stopped them in the G0/G1 phase. 71,72 Therefore, it was concluded that both b-lapachone and EF generated ROS, but instead of accelerating cell migration, excessive ROS caused certain damage to cells, which in turn decreased the wound-healing rate as seen in Fig.…”