Rapid nongenomic signaling by estrogens (Es), initiated near the cell membrane, provides new explanations for the potent actions of environmental chemicals that imperfectly mimic physiological Es. These pathways can affect tumor growth, stabilization, or shrinkage via a number of signaling streams such as activation/inactivation of mitogen-activated protein kinases and caspases, generation of second messengers, and phospho-triggering of cyclin instability. Though prostate cancers are better known for their responsiveness to androgen deprivation, ∼17% of late stage tumors regress in response to high dose natural or pharmaceutical Es; however, the mechanisms at the cellular level are not understood. More accurate recent measurements show that estradiol (E2) levels decline in aging men, leading to the hypothesis that maintaining young male levels of E2 may prevent the growth of prostate cancers. Major contributions to reducing prostate cancer cell numbers included low E2 concentrations producing sustained ERK phospho-activation correlated with generation of reactive oxygen species causing cancer cell death, and phospho-activation of cyclin D1 triggering its rapid degradation by interrupting cell cycle progression. These therapeutic actions were stronger in early stage tumor cells (with higher membrane estrogen receptor levels), and E2 was far more effective compared to diethylstilbestrol (the most frequently prescribed E treatment). Xenoestrogens (XEs) exacerbated the growth of prostate cancer cells, and as we know from previous studies in pituitary cancer cells, can interfere with the nongenomic signaling actions of endogenous Es. Therefore, nongenomic actions of physiological levels of E2 may be important deterrents to the growth of prostate cancers, which could be undermined by the actions of XEs.
Keywords: Cyclin D1; ERK activation; JNK activation; Membrane estrogen receptors; ROS; Signaling.
Published by Elsevier Inc.