Role of connexin 43 in cadmium-induced proliferation of human prostate epithelial cells

Abstract

Connexins (Cxs), the subunits of gap junction channels, are involved in many physiological processes. Aberrant control of Cxs and gap junction intercellular communication may contribute to many diseases, including the promotion of cancer. Cd exposure is associated with increased risk of human prostate cancer and benign prostatic hyperplasia. The roles of Cxs in the effects of Cd on the prostate have, however, not been reported previously. In this study, the human prostate epithelial cell line RWPE-1 was exposed to Cd. A low dose of Cd stimulated cell proliferation along with a lower degree of gap junction intercellular communication and an elevated level of the protein Cx43. Cd exposure increased the levels of intracellular Ca and phosphorylated Cx43 at the Ser368 site. Knockdown of Cx43 using siRNA blocked Cd-induced proliferation and interfered with the Cd-induced changes in the protein levels of cyclin D1, cyclin B1, p27 (p27) and p21 (p21). The increase in Cx43 expression induced by Cd was presumably mediated by the androgen receptor, because it was abolished upon treatment with the androgen receptor antagonist, flutamide. Thus, a low dose of Cd promotes cell proliferation in RWPE-1, possibly mediated by Cx43 expression through an effect on cell cycle-associated proteins. Cx43 might be a target for prostatic diseases associated with Cd exposure. Copyright © 2017 John Wiley & Sons, Ltd.

Antiapoptotic Effects of Continuous Training and Selenium Consumption on the Liver Tissue of Cadmium-Exposed Rats

“…This protein plays a key role in cell proliferation, cell growth regulation, and mitochondrial activity fluctuations (19). Based on research conducted on prostatic epithelial cells, cadmium reduces the protein level of cyclin D (20), which is parallel with the findings of the present study.…”

Connexins and Gap Junctions in Cancer of the Urinary Tract

“…Cadmium or cadmium salts, respectively, also inhibit the gap junction-mediated communication between rat liver cells (cell line BRL 3A), as shown in a scrape loading assay [60]. Cadmium and GJIC were investigated using a parachute assay in prostate cells [61]. A low dose of CdCl 2 stimulated cell proliferation, increased the expression of connexin 43, and reduced the dye transfer between donor and acceptor cells by half.…”

Cell junctions in the prostate: an overview about the effects of Endocrine Disrupting Chemicals (EDCS) in different experimental models

“…Recently, Zhang et al [94] related the Cx-43 with oncogenicity and metastatic potential in four different prostate cancer cells lines. Considering this, Liu et al [95] demonstrated that cadmium (5-10 μM) was able to increase Cx-43 expression, probably by a mechanism linked to androgen receptor (AR), and promoted proliferation in RWPE-1 cells. The authors concluded that cadmium incites cell proliferation, mediated by Cx-43 expression through an effect on cell cycle-associated proteins [95].…”

“…Considering this, Liu et al [95] demonstrated that cadmium (5-10 μM) was able to increase Cx-43 expression, probably by a mechanism linked to androgen receptor (AR), and promoted proliferation in RWPE-1 cells. The authors concluded that cadmium incites cell proliferation, mediated by Cx-43 expression through an effect on cell cycle-associated proteins [95]. This relationship between AR and Cx-43 is in agreement with reviewed data by Boucher et al [29] that presented studies showing an increase in Cx-43 expression after pharmacological or physical castration, being associated with increased expression of apoptotic markers and reduced cell proliferation.…”