Aberrant Expression of ZIP and ZnT Zinc Transporters in UROtsa Cells Transformed to Malignant Cells by Cadmium

Soisungwan Satarug,Scott H Garrett,Seema Somji,Mary Ann Sens,Donald A Sens

doi:10.3390/stresses1020007

Soisungwan Satarug, Scott H Garrett + Show 3 more

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https://doi.org/10.3390/stresses1020007

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Abstract

Maintenance of zinc homeostasis is pivotal to the regulation of cell growth, differentiation, apoptosis, and defense mechanisms. In mammalian cells, control of cellular zinc homeostasis is through zinc uptake, zinc secretion, and zinc compartmentalization, mediated by metal transporters of the Zrt-/Irt-like protein (ZIP) family and the Cation Diffusion Facilitators (CDF) or ZnT family. We quantified transcript levels of ZIP and ZnT zinc transporters expressed by non-tumorigenic UROtsa cells and compared with those expressed by UROtsa clones that were experimentally transformed to cancer cells by prolonged exposure to cadmium (Cd). Although expression of the ZIP8 gene in parent UROtsa cells was lower than ZIP14 (0.1 vs. 83 transcripts per 1000 β-actin transcripts), an increased expression of ZIP8 concurrent with a reduction in expression of one or two zinc influx transporters, namely ZIP1, ZIP2, and ZIP3, were seen in six out of seven transformed UROtsa clones. Aberrant expression of the Golgi zinc transporters ZIP7, ZnT5, ZnT6, and ZnT7 were also observed. One transformed clone showed distinctively increased expression of ZIP6, ZIP10, ZIP14, and ZnT1, with a diminished ZIP8 expression. These data suggest intracellular zinc dysregulation and aberrant zinc homeostasis both in the cytosol and in the Golgi in the transformed UROtsa clones. These results provide evidence for zinc dysregulation in transformed UROtsa cells that may contribute in part to their malignancy and/or muscle invasiveness.

Highlights

Cadmium (Cd) is one of the environmental toxicants of continuing public health concern worldwide due to its persistence, widespread exposure, and wide-ranging adverse health effects, cancer risk included [1,2,3]
Works in other laboratories have demonstrated a role for ZIP8 and ZIP14 in Cd2+ uptake by many other cell types [29,30], while ZnT1 could be responsible for Cd2+ excretion [32]
Lower expression levels of ZIP8 than ZIP14 suggested that ZIP14 and ZnT1 could potentially be involved in Cd accumulation and cytotoxicity of Cd in this cell line

Summary

Introduction

Cadmium (Cd) is one of the environmental toxicants of continuing public health concern worldwide due to its persistence, widespread exposure, and wide-ranging adverse health effects, cancer risk included [1,2,3]. Bladder cancer ranks the sixth most common cancer in the U.S, with annual incidence rates of 30 to 33 cases per 100,000. One third of bladder cancer cases manifested as non-papillary tumors with high invasive and metastasis potential, while two thirds manifested as non-invasive, resettable papillary tumors, with recurrence rates between 30% and 70% [5]. Such high recurrence rates necessitate frequent cystoscopy and urine cytology [5], making bladder cancer the fifth highest cancer treatment and the highest care cost per patient in the U.S [8,9]

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