Cadmium down-regulates expression of XIAP at the post-transcriptional level in prostate cancer cells through an NF-κB-independent, proteasome-mediated mechanism

In 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.Selection of cadmium-resistant cells could represent an adaptive survival mechanism that may contribute to progression of prostatic malignancies.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. Exposure to cadmium and cadmium-containing compounds primarily occurs in the workplace (e. g. mining, smelting, processing, product formulations, and battery manufacturing). Meanwhile, non-occupational exposure is also widespread and stems from foods and tobacco smoke [1]. Furthermore, cadmium has been detected in significant amounts in all tested zinc-containing dietary supplements [2]. Cadmium has a long biological half-life (>25 years), due to the flat kinetics of its excretion [3]. 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. The cells transformed by cadmium demonstrate morphological alterations, anchorage-independent growth in soft agar, and formation of tumors when transplanted into SCID mice [6]. In addition, cadmium chloride has