Cisplatin resistance mediated by cooper export pathways

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DESCRIPTION (provided by applicant): The ability of the copper (Cu) exporters ATP7A and ATP7B to regulate tumor cell sensitivity to the platinum-containing drugs by altering their intracellular sequestration and efflux has now been demonstrated in multiple experimental systems. The overall goal of this project is to determine the mechanism by which ATP7A and ATP7B mediate the efflux of cisplatin, carboplatin and oxaliplatin from ovarian carcinoma cells. Our hypothesis is that at clinically relevant concentrations, the platinum drugs enter the cell, are distributed to various subcellular compartments and are exported from the cell using transporters and chaperones that have evolved to control Cu homeostasis. A corollary to this hypothesis is that, as for Cu, these PI-type ATPases function to detoxify the Pt drugs by sequestering them into or onto vesicles of the secretory pathway that are eventually exported from the cell. The specific aims are to: 1) determine whether ATP7A and ATP7B bind and transport cisplatin, carboplatin and oxaliplatin into secretory vesicles; 2) investigate the ability of the Pt drugs to bind to the Cu-binding motif in the metal binding sequences of ATP7A, ATP7B and ATOX1 proteins; and, 3) determine whether the Cu chaperone ATOX1 is essential to the ability of ATP7A and ATP7B to mediate Pt drug resistance, sequestration, and export in living cells. Careful dissection of the mechanism by which the Cu efflux transporters modulate the export of the Pt drugs is expected to offer insight into why cisplatin, carboplatin and oxaliplatin differ in their efficacy and toxicity, and to identify strategies for improving the therapeutic index of these agents. These studies will also further elucidate the mechanisms that mediate resistance to this important class of chemotherapeutic agents and suggest clinically relevant strategies for reversing resistance.