Role of ZIP8 in regulation of cisplatin sensitivity through Bcl-2

Abstract

ZIP8 is a membrane transporter that facilitates the uptake of divalent metals (e.g., Zn, Mn, Fe, Cd) and the mineral selenite in anionic form. ZIP8 functionality has been recently reported to regulate cell proliferation, migration and cytoskeleton arrangement, exhibiting an essential role for normal physiology. In this study, we report a ZIP8 role in chemotherapy response. We show ZIP8 regulates cell sensitivity to the anti-cancer drug cisplatin. Overexpression of ZIP8 in mouse embryonic fibroblast (MEF) cells induces cisplatin sensitivity, while knockout of ZIP8 in leukemia HAP1 cells leads to cisplatin resistance. In ZIP8 altered cells and transgenic mice, we show cisplatin is not a direct ZIP8 substrate. Further studies demonstrate that ZIP8 regulates anti-apoptotic protein Bcl-2. ZIP8 overexpression decreases Bcl-2 levels in cultured cells, mice lung and liver tissue while loss of ZIP8 elevates Bcl-2 expression in HAP1 cells and liver tissue. We also observe that ZIP8 overexpression modulates cisplatin-induced cell apoptosis, manifested by the increased protein level of cleaved Caspase-3. Since Bcl-2 elevation was previously discovered to induce cisplatin drug resistance, our results suggest ZIP8 may modulate cisplatin drug responses as well as apoptosis through Bcl-2. We therefore conclude ZIP8 is a new molecule to be involved in cisplatin drug responses and is predicted as a genetic factor to be considered in cisplatin therapy.

Keywords: Apoptosis; Bcl-2; Cisplatin; Drug-resistance; Transporter; ZIP8.