Cisplatin (DDP) is highly effective for the initial therapy of a variety of human cancers, but resistance emerges quickly during treatment. We have discovered that human ovarian carcinoma cells selected for resistance to DDP are cross resistant to copper (Cu) and that cells selected for resistance to Cu are cross-resistant to DDP. Our hypothesis is that DDP enters the cell, is distributed to various subcellular compartments, and is exported from the cell by transporters and chaperones that normally mediate Cu homeostasis. Such transporters and chaperones normally protect Cu from reacting with other molecules during its distribution. Our hypothesis is that these pteins also protect DDP from reacting with intracellular thiols while it travels between the cell surface and the nucleus, thus explaining how DDP can kill cells even when its concentration is 3 orders of magnitude lower than that of intracellular thiols. This project focuses specifically on ATP7A, a pump that is known to sequester Cu from the cytoplasm into the trans-Golgi network for subsequent export from the cell, It is the overall aim of this project to determine how ATP7A regulates sensitivity to DDP and what role ATP7A plays in acquired resistance to this drug.
The specific aims are directed at the following questions: 1) Does ATP7.A alter sensitivity by modulating the cellular pharmacology of DDP? 2) Is DDP actually a substrate for the ATP7A transporter? 3) What structural components of ATP7A are essential to its ability to mediate DDP resistance? 4) For what classes of Pt-containing drugs is ATP7.A a major determinant of sensitivity 5) Does increased expression of ATP7.A account for acquired DDP resistance in human tumor cells? The hypothesis that DDP is a substrate for Cu-binding proteins is an entirely new concept in the field. Ifit is correct, then alterations in many of the other transporters and chaperones that normally mediate Cu homeostasis may also play a role in resistance to DDP and several other heavy metals. The results of these studies are expected to be of fundamental importance in identifying novel strategies for overcoming intrinsic resistance and reversing acquired resistance to this very important chemotherapeutic agent.
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