Cancer is the second leading cause of death in the United States. Despite remarkable advances in the use of small molecule- and antibody-based approaches to cancer treatment, many chemotherapeutic agents remain in widespread use decades after their discovery. The platinum-containing drug cisplatin is widely used for the treatment of solid tumors, and is particularly effective against germ cell tumors. Cisplatin exerts its cytotoxic effects through the formation of intrastrand crosslinks on DNA; the DNA damage triggers intracellular signaling networks that ultimately promote cell death. Cisplatin entry into cells is mediated by the transmembrane copper transporter Ctr1; to date, this molecule has not otherwise been thought to contribute to cisplatin's mechanism of action, nor has Ctr1 gain- or loss-of-function been implicated in oncogenesis or tumor progression. Our laboratory has demonstrated that Ctr1 additionally functions as a signaling molecule, and is required for mesoderm formation in the amphibian embryo as a component of the intracellular network downstream of the Fibroblast Growth Factor (FGF) receptor; furthermore, loss of Ctr1 inhibits the differentiation of mammalian embryonic stem (ES) cells. Surprisingly, we have found that cisplatin treatment phenocopies Ctr1 knockdown in amphibian differentiation assays, and induces precocious differentiation of mesoderm in human induced pluripotent stem (iPS) cells; these data suggest that cisplatin exerts its anticancer effects in germ cell tumors in part via regulation of cellular differentiation, possibly as a modulator of Ctr1 signaling. Experiments proposed in this application will determine whether the therapeutic effects of cisplatin are mediated in part by alteration of signal flow through Ctr1. We will identify the mechanisms underlying cisplatin-mediated regulation of differentiation in amphibian and mammalian cells. These studies should provide important insights into the potential treatment of germ cell and other solid tumors, and will test the hypothesis that Ctr1 is an important target for future chemotherapy regimens.
Experiments proposed in this application will determine whether the therapeutic effects of the anticancer drug cisplatin are mediated in part via alteration of signal flow through the copper transporter Ctr1. These studies should provide important insights into the etiology and potential treatment of germ cell and other solid tumors, and will test the hypothesis that Ctr1 is an important target for future chemotherapy regimens.
