Abstract
BackgroundCadmium has been classified as a human carcinogen, affecting health through occupational and environmental exposure. Cadmium has a long biological half-life (>25 years), due to the flat kinetics of its excretion. The prostate is one of the organs with highest levels of cadmium accumulation. Importantly, patients with prostate cancer appear to have higher levels of cadmium both in the circulation and in prostatic tissues.ResultsIn the current report, we demonstrate for the first time that cadmium down-regulates expression of the X-linked inhibitor of apoptosis protein (XIAP) in prostate cancer cells. Cadmium-mediated XIAP depletion occurs at the post-transcriptional level via an NF-κB-independent, proteasome-mediated mechanism and coincides with an increased sensitivity of prostate cancer cells to TNF-α-mediated apoptosis. Prolonged treatment with cadmium results in selection of prostate cancer cells with apoptosis-resistant phenotype. Development of apoptosis-resistance coincides with restoration of XIAP expression in cadmium-selected PC-3 cells.ConclusionsSelection of cadmium-resistant cells could represent an adaptive survival mechanism that may contribute to progression of prostatic malignancies.
Highlights
Cadmium has been classified as a human carcinogen, affecting health through occupational and environmental exposure
Given that X-linked inhibitor of apoptosis protein (XIAP) contains three zinc-binding baculovirus IAP repeat (BIR) domains and a zincbinding really interesting new gene (RING) domain, we examined the impact of cadmium on the expression of XIAP in prostate cancer cell lines
To test the possibility that cadmium modulates XIAP expression at the transcriptional level, we examined the levels of XIAP mRNA in PC-3 and DU-145 cells incubated with cadmium by real-time PCR
Summary
Cadmium has been classified as a human carcinogen, affecting health through occupational and environmental exposure. Patients with prostate cancer appear to have higher levels of cadmium both in the circulation and in prostatic tissues. Cadmium is a ubiquitous environmental pollutant that is classified as a human carcinogen by the International Agency for Research on Cancer and the National Toxicology Program. The prostate is one of the organs with highest levels of cadmium accumulation [4,5]. The carcinogenic properties of cadmium have been extensively studied, using in vitro cell culture and in vivo animal models. In vitro studies have reported malignant transformation of non-tumorigenic human prostate epithelial cells following cadmium exposure. Patients with prostate cancer appear to have higher levels of cadmium both in the circulation and in prostatic tissues [10]. Aberrant gene expression resulting in increased cell proliferation or blockade of apoptosis may be the mechanisms responsible for cadmium-mediated carcinogenesis [11]
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