2,2-Bis(4-Chlorophenyl)-1,1-Dichloroethylene Stimulates Androgen Independence in Prostate Cancer Cells through Combinatorial Activation of Mutant Androgen Receptor and Mitogen-Activated Protein Kinase Pathways

Abstract

Therapy resistance represents a major clinical challenge in disseminated prostate cancer for which only palliative treatment is available. One phenotype of therapy-resistant tumors is the expression of somatic, gain-of-function mutations of the androgen receptor (AR). Such mutant receptors can use noncanonical endogenous ligands (e.g., estrogen) as agonists, thereby promoting recurrent tumor formation. Additionally, selected AR mutants are sensitized to the estrogenic endocrine-disrupting compound (EDC) bisphenol A, present in the environment. Herein, screening of additional EDCs revealed that multiple tumor-derived AR mutants (including T877A, H874Y, L701H, and V715M) are sensitized to activation by the pesticide 2,2-bis(4-chlorophenyl)-1,1-dichloroethylene (DDE), thus indicating that this agent may impinge on AR signaling in cancer cells. Further investigation showed that DDE induced mutant AR recruitment to the prostate-specific antigen regulatory region, concomitant with an enhancement of target gene expression, and androgen-independent proliferation. By contrast, neither AR activation nor altered cellular proliferation was observed in cells expressing wild-type AR. Activation of signal transduction pathways was also observed based on rapid phosphorylation of mitogen-activated protein kinase (MAPK) and vasodilator-stimulated phosphoprotein, although only MAPK activation was associated with DDE-induced cellular proliferation. Functional analyses showed that both mutant AR and MAPK pathways contribute to the proliferative action of DDE, as evidenced through selective abrogation of each pathway. Together, these data show that exposure to environmentally relevant doses of EDCs can promote androgen-independent cellular proliferation in tumor cells expressing mutant AR and that DDE uses both mutant AR and MAPK pathways to exert its mitogenic activity.

Organochlorine pesticides and prostate cancer, Is there an association? A meta-analysis of epidemiological evidence

“…Because of the difficulty in examining the proposed association in humans, in vitro prostate cell culture and animal models have provided a basis for studying underlying mechanisms [53,56]. It was suggested that DDT and its metabolites mimic the action of estrogens and antagonize the action of androgens [14]. The latter was found to be via binding competitively to androgen receptors and inhibiting 5a-reductase, the enzyme responsible for converting testosterone to the more potent androgen dihydrotestosterone [57].…”

“…Cell lines, animal, and toxicological studies have suggested different mechanisms of action of various OCPs on the development of PC [13,14]. Interference with endogenous estrogenic or androgenic pathways as agonists or antagonists has been proposed [15].…”

Bisphenol A may reduce the efficacy of androgen deprivation therapy in prostate cancer

“…There is in an vitro evidence indicating plausible modes of action of BPA-mediated reduced therapeutics efficacy for prostate cancer [28][29][30]. Multiple lines of evidence indicate that the key event resulting in BPA-facilitated therapeutic bypass of prostate cancer cells is the binding to and activation of tumor-derived mutant ARs by BPA, resulting in BPA:AR complex-mediated cellular proliferation [28][29][30]46].…”

“…Multiple lines of evidence indicate that the key event resulting in BPA-facilitated therapeutic bypass of prostate cancer cells is the binding to and activation of tumor-derived mutant ARs by BPA, resulting in BPA:AR complex-mediated cellular proliferation [28][29][30]46].…”

“…It has been shown that environmental compounds, such as BPA (1 nM) and dichlorodiphenyldichloroethylene (DDE; 10 pM), can activate tumor-derived mutant ARs and induce AR-dependent proliferation of the cancer cell in the absence of natural mitogenic stimulus [28][29][30]. These studies shift the attention from compounds causing, or increasing the susceptibility to, prostate cancer to assessing the impact of these agents on the progression and treatment of established disease.…”