The Evolving Role for Zinc and Zinc Transporters in Cadmium Tolerance and Urothelial Cancer

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.

Is Cadmium Toxicity Tissue-Specific? Toxicogenomics Studies Reveal Common and Specific Pathways in Pulmonary, Hepatic, and Neuronal Cell Models

“…Cd has a similar ionic radius to that of calcium (Ca), and similar electronegativity to that of zinc (Zn) leading to the uptake of this non-essential metal by the same transporters and pathways used by essential elements such as Ca, Zn, iron (Fe) and manganese (Mn) [17]. Within mammalian cells, this molecular mimicry and the chemical properties lead to the substitution for Ca in cellular signaling, the displacement of Zn in the zinc-proteome, the binding to essential sites of biomolecules (e.g., SH-groups) thus impacting the levels of second messengers and transcription factors, inhibiting DNA repair systems and inactivating tumor suppressors such as p53 [16,[18][19][20][21].…”

Toxicity Tolerance in the Carcinogenesis of Environmental Cadmium

“…Other types of cancer found to be associated with Cd exposure were endometrial cancer [117], acute myeloid leukemia [118], urinary bladder cancer [119], oral and gastrointestinal carcinomas [120,121], and nasopharyngeal and pharyngeal cancers [122].…”

Evidence for Ovarian and Testicular Toxicities of Cadmium and Detoxification by Natural Substances

“…Consequently, several mechanisms have been postulated, such as altered gene expression, apoptosis, oxidative stress, aberrant cell signaling, and disruption of endocrine system [65,66]. However, it is noteworthy that Cd must first enter cells to cause toxicity and that members of Zn transporters of the Zrt-and Irt-related protein (ZIP) family, such as ZIP8 and ZIP14, have been shown to mediate Cd uptake by cells [67][68][69]. Indeed, ZIP8 has been shown to be involved in Cd-induced testicular injury [70][71][72].…”