Maintaining optimal intracellular zinc (Zn) concentration is crucial for critical cellular functions. Depleted Zn has been associated with prostate cancer (PCa) progression. Solute carrier family 30 (SLC30A) proteins maintain cytoplasmic Zn balance by exporting Zn out to the extracellular space or by sequestering cytoplasmic Zn into intracellular compartments. In this study, we determined the involvement of Zn-exporters, SLC30A 1–10 in PCa, in the context of racial health disparity in human PCa samples obtained from European-American (EA) and African-American (AA) populations. We also analyzed the levels of Zn-exporters in a panel of PCa cells derived from EA and AA populations. We further explored the expression profile of Zn-exporters in PCa using Oncomine database. Zn-exporters were found to be differentially expressed at the mRNA level, with a significant upregulation of SLC30A1, SLC30A9 and SLC30A10, and downregulation of SLC30A5 and SLC30A6 in PCa, compared to benign prostate. Moreover, Ingenuity Pathway analysis revealed several interactions of Zn-exporters with certain tumor suppressor and promoter proteins known to be modulated in PCa. Our study provides an insight regarding Zn-exporters in PCa, which may open new avenues for future studies aimed at enhancing the levels of Zn by modulating Zn-transporters via pharmacological means.

Optimal intracellular zinc concentration is essential for many cellular functions as it serves as a catalytic and/or structural cofactor for a variety of proteins. Although, a number of proteins are tangled in regulating cellular zinc homeostasis, the most important are two protein families of zinc transporters, 14 members of solute carrier family 39 (SLC39A) and 10 members of solute carrier family 30 (SLC30A). These two families are known to transport zinc into- and out of- the cytoplasm, respectively. Prostate cells accumulate a high amount of zinc to sustain a metabolic condition unique to the prostate which is characterized by a truncation of the Krebs cycle and production of high amounts of citrate. Zinc depletion has frequently been noted in the progression of prostate cancer (PCa). Whether zinc transporters are a steering cause of zinc depletion in PCa development and progression and/or are key determinants in the racial disparity in PCa is not well studied. In this study, we determined the connection of zinc transporters (SLC39A 1-14 and SLC30A 1-10) in PCa, in the perspective of racial health disparity in human PCa samples taken from African-American (AA) and European-American (EA) patients and compared them with respective adjacent benign samples. We also assessed the mRNA level of zinc transporters in normal prostate epithelial cells (NrPEC and RWPE1) and among PCa cells derived from AA (MDA PCa 2b, E006AA-PAR, E006AA-HT) and EA patients (DU145, PC3, 22Rν1, LNCaP, C4-2B). In addition, we performed a dataset analysis of the Oncomine database for differential expression profile of zinc transporters in PCa versus normal prostate. We found that SLC39As mRNA levels were differentially expressed in PCa with a significant downregulation of SLC39A1, SLC39A10, SLC39A11, SLC39A13 and SLC39A14, and upregulation of SLC39A3, SLC39A5, SLC39A6 and SLC39A8. Further, SLC30As showed a significant downregulation of SLC30A5 and SLC30A6 and upregulation of SLC30A1, SLC30A9 and SLC30A10, in PCa. Further, compared to EA samples, the AA PCa showed an increasing trend of SLC39A5, SLC39A6 and SLC30A9. In addition, compared to AA samples, the EA PCa showed a trend of increasing SLC30A1 and SLC30A9 and decreasing SLC39A10. These data provide evidence that the zinc transporters may be linked to racial disparity of PCa in AA versus EA. Moreover, Ingenuity Pathway Analysis revealed regulatory interactions between zinc transporters and tumor suppressor/promoter genes proven to be modulated in PCa. These genes are HOXB13, ELAVL1, DIRAS3, ALPP, CSF2, CCL4, INSR, AKT, IL6, TGFBP1, CHI3L1, EGFR and HNF4A. Overall, our study provides interesting data about the expression profiles of zinc transporters and their interaction with tumor suppressor and promoter genes in PCa, which may offer novel strategies for the management of PCa by pharmacologically modulating zinc transporters. Citation Format: Chandra K. Singh, Kareem M. Malas, Caitlin Tydrick, Kenneth A. Iczkowski, Nihal Ahmad. Role of zinc transporters in prostate cancer and a potential association with racial disparity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4139. doi:10.1158/1538-7445.AM2017-4139