Abstract
Cadmium (Cd) is an environmental toxicant with serious public health consequences due to its persistence within arable soils, and the ease with which it enters food chains and then, accumulates in human tissues to induce a broad range of adverse health effects. The present review focuses on the role of zinc (Zn), a nutritionally essential metal, to protect against the cytotoxicity and carcinogenicity of Cd in urinary bladder epithelial cells. The stress responses and defense mechanisms involving the low-molecular-weight metal binding protein, metallothionein (MT), are highlighted. The efflux and influx transporters of the ZnT and Zrt-/Irt-like protein (ZIP) gene families are discussed with respect to their putative role in retaining cellular Zn homeostasis. Among fourteen ZIP family members, ZIP8 and ZIP14 mediate Cd uptake by cells, while ZnT1 is among ten ZnT family members solely responsible for efflux of Zn (Cd), representing cellular defense against toxicity from excessively high Zn (Cd) intake. In theory, upregulation of the efflux transporter ZnT1 concomitant with the downregulation of influx transporters such as ZIP8 and ZIP14 can prevent Cd accumulation by cells, thereby increasing tolerance to Cd toxicity. To link the perturbation of Zn homeostasis, reflected by the aberrant expression of ZnT1, ZIP1, ZIP6, and ZIP10, with malignancy, tolerance to Cd toxicity acquired during Cd-induced transformation of a cell model of human urothelium, UROtsa, is discussed as a particular example.
Highlights
Cadmium (Cd) is a redox inert divalent metal that has no known biological role in humans [1,2,3,4]
Of note, dysregulated cellular Zn homeostasis and aberrant expression of ZnT1, ZIP1, ZIP4, ZIP6, ZIP7, and ZIP10 have increasingly been observed in various types of cancer, including urinary bladder, prostate, pancreatic and breast cancers [25,26,27,28,29,30]
Increased expression of ZnT1, ZnT4, ZnT6 and ZnT10 concomitant with a reduction in expression of ZIP1, ZIP8 and ZIP14 were seen in one transformed UROtsa clone exhibiting a high invasiveness propensity
Summary
Cadmium (Cd) is a redox inert divalent metal that has no known biological role in humans [1,2,3,4]. The perturbation of cellular Zn homeostasis may account, in large part, for the wide range of diversity of the toxic effects of Cd because of the key role of Zn in the regulation of cell growth, differentiation, apoptosis, and defense mechanisms. Emergent evidence for tolerance to Cd toxicity through the upregulation of metal efflux transporters concomitant with the downregulation of influx transporters is emphasized together with data from in vitro studies, demonstrating that long-term exposure to low-level environmental Cd, producing blood and urinary Cd at concentrations no greater than 1 μM, could cause cells to undergo malignant transformation. Influx, efflux, subcellular compartmentalization (storage) and trafficking of Zn are coordinately regulated These processes are mediated by metal transporters, encoded by two gene families—the Solute-Linked Carrier 30A (SLC30A) and the Solute-Linked Carrier 39A (SLC39A) [23,24]. Of note, dysregulated cellular Zn homeostasis and aberrant expression of ZnT1, ZIP1, ZIP4, ZIP6, ZIP7, and ZIP10 have increasingly been observed in various types of cancer, including urinary bladder, prostate, pancreatic and breast cancers [25,26,27,28,29,30]
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