Chronic cadmium exposure induces epithelial mesenchymal transition in prostate cancer cells through a TGF-β-independent, endoplasmic reticulum stress induced pathway.

Abstract

In this study, we aimed to elucidate the role of chronic cadmium (Cd) exposure in epithelial-mesenchymal transition (EMT) and thus malignant phenotypic changes of prostate cancer cells. Prostate cancer cells (PC-3 and DU145) were exposed to a non-toxic level (0.5 or 2 μM) of Cd for up to 3 months, which resulted in significantly promoted migration and invasion of the cells. These phenotypic changes were considered to be the consequence of enhanced EMT as evidenced by diminished expression of E-cadherin and increased vimentin expression. Regarding the mechanisms of Cd-induced EMT, we found Smad3 was activated but without upregulation of TGF-β. Alternatively, we found endoplasmic reticulum (ER) stress of prostate cancer cells was significantly evoked, which was parallel with the increased reactive oxygen species (ROS). Removal of ROS by N-acetylcysteine significantly reduced ER stress in prostate cancer cells, followed by the decrease of Smad3 phosphorylation and expression of nuclear Snail, resulting in the inhibition of EMT and malignant phenotypic changes of prostate cancer cells. These findings indicated a new TGF-β independent, ROS-mediated ER stress/Smad signaling pathway in chronic Cd exposure-induced EMT of prostate cancer cells, which could be a novel mechanism involved in cadmium-mediated cancer cells malignant transformation. Accordingly, ROS-induced ERs may become a novel preventive and therapeutic target for cancer.

• Authors: Weirong Hu, Mizhen Xia, Cheng Zhang, Bingdong Song, Zhengmei Xia, Chunyu Guo, Yingying Cui, Weiying Jiang, Shicheng Zhang, Dexiang Xu, Jun Fang
• Journal: Toxicology letters (Toxicol Lett) Vol. 353 Pg. 107-117 (Dec 15 2021) ISSN: 1879-3169 [Electronic] Netherlands
• PMID: 34687772 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 Elsevier B.V. All rights reserved.

Chemical References

• Reactive Oxygen Species
• SMAD3 protein, human
• Smad3 Protein
• Transforming Growth Factor beta
• Cadmium

Topics

• Cadmium (toxicity)
• Cell Movement (drug effects)
• Endoplasmic Reticulum Stress (drug effects)
• Epithelial-Mesenchymal Transition (drug effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Male
• PC-3 Cells
• Prostatic Neoplasms (metabolism)
• Reactive Oxygen Species (metabolism)
• Smad3 Protein (genetics, metabolism)
• Transforming Growth Factor beta (genetics, metabolism)