Despite advances in cancer genetics and treatment, anticancer drug resistance remains a formidableproblem and challenge to oncologists and researchers alike. The long-term goat of this project has been the dissection of mechanisms of tumor multidrug resistance. It was known previously that anticancer drug resistance at the cellular level, even to a single agent, is a multifactorial phenomenon;multiple genetic changes can occur in a tumor cell selected for resistance to any particular cytotoxic agent. Complementing this view, we have learned more recently that the putative targets of anticancer agents and mediators of their actions play complex roles in cellular physiology and drug responsiveness. For example, topoisomerases undergo post- translational modifications in response to drug treatments, and these modifications have revealed a complex signaling pathway involving sumoylation that is also involved in drug responses. Further, with regard to ABC transporters, which mediate multidrug resistance, we have learned that one member of this class, MRP1/ABCC1, appears to be regulated by the signaling molecule Notch-1, and that another member, BCRP/ABCG2, is regulated by estrogen. Accordingly, study of novel mechanisms of regulation of ABC protein expression may afford unique methods to circumvent drug resistance. Thus, expanding on the historical focus of our laboratory efforts in ABC transporters and topoisomerases, we wish to build on the new knowledge of the past few years and on the progress we have made in the prior funding period to test the hypothesis that novel regulatory mechanisms for expression of topoisomerases and ABC proteins affect anticancer drug responses and offer insights into new therapeutic paradigms. Building on work done in the prior funding period, I offer here a focused application and propose the following specific aims to test our hypothesis: (1) Define the molecular mechanisms of regulation of topoisomerases in mammalian tumors and drug-mediated cytotoxiciry through these enzymes;(2) Define the role of Ubc9 and protein sumoylation in anticancer drug responsiveness;and (3) Define the molecular mechanisms of novel regulation by Notch-1 of expression of the ABC transporter,MRP1/ABCC1.
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