Rapid, Nongenomic Signaling Effects of Several Xenoestrogens Involved in Early- Vs. Late-Stage Prostate Cancer Cell Proliferation

Xenoestrogens (XEs) are exogenous mimics capable of binding to estrogen receptors (ERs), competing with/disrupting the actions of physiological estrogens, and promoting tumor growth in the prostate and other endocrine tissues. Humans are exposed to numerous XEs including environmental contaminants such as plastics monomer bisphenol A (BPA), and dietary phytoestrogens such as coumestrol and genistein from soy, and resveratrol, highest in red grapes. There is growing interest in the ability of phytoestrogens to prevent or treat tumors. We previously reported that multiple cellular mechanisms influence the number of prostate cancer cells after estradiol or diethylstilbestrol treatment. We now examine the effect of these XEs on signaling mechanisms that alter the number of LAPC-4 (androgen-dependent) and PC-3 (androgen-independent) cells at environment- and diet-relevant concentrations. Coumestrol and genistein both increased the number of LAPC-4 and PC-3 cells dramatically. Rapid alterations of phospho- and total-cyclin D1 levels most closely correlated with the XE-induced changes in cell numbers. Sustained activation (phosphorylation) of the extracellular signal-regulated kinases 1 and 2 as a prelude to generation of reactive oxygen species also partially contributed to the XE's effects on cell numbers. Early-stage cells expressed higher levels of all 3 ERs (including those in membranes) than did late-stage cells; ER subtypes were variably involved in the signaling responses. Taken together, these results show that each XE can elicit its own signature constellation of signaling responses, highlighting the importance of managing exposures to both environmental and dietary XEs for existing prostate tumors. These mechanisms may offer new cellular targets for therapy.