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Underlying Mechanism Identified for Prostate Cancer Caused by Cadmium

By BiotechDaily International staff writers
Posted on 18 Apr 2012
The widespread, extremely toxic heavy metal cadmium, classified as a Group 1 human carcinogen by the International Agency for Research on Cancer and the US National Toxicology Program, has now been shown to induce apoptosis resistance related to carcinogenesis in human prostrate cells.

An established lung carcinogen in humans, cadmium has also been suspected of playing a role in the induction and the development of prostate cancer, one of the most commonly diagnosed cancers in men. Though multiple molecular targets have been identified, which suggests that more than a single pathway may be involved, specific molecular events of the underlying mechanism(s) have remained elusive. It has been hypothesized that a key factor in cadmium-induced malignant transformation is acquisition of apoptotic resistance. In the present study, published online March 20, 2012, in the journal PLoS ONE, scientists investigated cultured cells derived from human prostate epithelium for effects of cadmium exposure on apoptosis and on the expression of some tumor suppressor proteins.

Initially, the normal RWPE-1 cell line was tested and compared with the response of its cadmium-transformed derivative CTPE. Subsequently, different prostate cancer cell lines were analyzed, including primary adenocarcinoma (22Rv1 and CWR-R1) and metastatic adenocarcinoma cells (LNCaP, PC-3, and DU145). Cells were treated for 24 hours with different concentrations of CdCl(2) , upon which apoptosis, cell cycle distribution, and expression of tumor suppressor proteins were analyzed. Concentrations relevant to human exposure were used: cadmium concentrations (10-30 µM) that are within the range that have been found in normal, hypertrophic, and malignant human prostate tissues and that, at the same time, are able to trigger apoptosis in cell culture systems.

Cellular response to cadmium was also evaluated after siRNA-mediated p53 silencing in wild type p53-expressing RWPE-1 and LNCaP cells, and after adenoviral p53 overexpression in p53-deficient DU145 and PC-3 cell lines. These and additional data showed that p53 silencing was able to suppress cadmium-induced apoptosis. The results demonstrated that cadmium can induce p53-dependent apoptosis in human prostate epithelial cells and suggest p53 mutation as a possible contributing factor for the acquisition of apoptotic resistance in cadmium prostatic carcinogenesis.

“In our study, we investigated the effects of cadmium exposure in normal and in tumor cells derived from human prostate tissue,” said Dr. Pier Paolo Claudio, lead scientist of the study and associate professor in the Biomedical Sciences Graduate Program and Department of Biochemistry and Microbiology in the Joan C. Edwards School of Medicine at Marshall University (Huntington, WV, USA). “The focus of work in our laboratory is to understand the molecular mechanisms governing malignant transformation in order to tailor novel therapeutic strategies. To effectively design novel biological drugs, a thorough understanding of the mechanism of cancer pathogenesis is required,” he added.

The authors, part of a collaborative effort between multiple institutions in Italy and the USA, noted that since the acquisition of apoptotic resistance appears to be crucial in cadmium-induced malignant transformation, further characterization of the pathways involved as well as a thorough comparative proteome analysis of the different prostate epithelial cells studied would significantly improve understanding of cadmium carcinogenesis in the prostate.

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