Nuclear Pore Complex Architecture and Drug Resistance in Ovarian Carcinomas

DESCRIPTION (provided by applicant): While ovarian carcinomas initially respond well to treatment with platinum drugs, the majority relapse and acquire resistance. In ovarian carcinomas, we have observed reductions of NUP62 in resected tumor tissue from ovarian carcinomas, and redistribution of NUP62 among subnuclear fields of nuclear pore complexes (NPCs). Further, enrichment of NUP62-depleted NPCs renders ovarian carcinoma cells resistant to cisplatin in culture. The studies suggest the hypothesis that survival advantages conferred by the enrichment of NUP62- and/or NUP214+ NPCs may be exploited by tumor cells. To advance this hypothesis, we propose: 1) To investigate alterations in the accumulation and distribution of NUP62 and NUP214 in ovarian carcinomas, and to decipher how these factors correspond to tumor parameters;and, to investigate how changes in expression or accumulation of either NUP62 or NUP214 influences distribution of the other nucleoporin among NPCs. 2) To investigate how knockdown of NUP62 confers resistance to cisplatin;specifically, to decipher how altering the distribution and prevelance of NUP62+/NUP214- and NUP62-/NUP214+ NPC populations influence survival signaling through NF-:B signaling pathways. The proposed studies impact the basic biology of epigenetic regulation and may also illuminate a new approach to improving the prognosis of ovarian carcinomas treated with platinum drugs. As the patterning and architecture of NPC populations influences the sensitivity of ovarian carcinoma cells to cisplatin, small molecules may be developed that modify NPC architecture to enhance its therapeutic effectiveness. These agents may be employed to reduce the number of cells that survive and/or become latent in response to therapy, and also to chemosensitize relapsed tumors that have acquired platinum resistance. PUBLIC HEALTH RELEVANCE: The proposed studies are concerned with a novel mechanism by which ovarian cancinoma cells acquire resistance to cisplatin. While ovarian tumors initially respond well to cisplatin and carboplatin, 70 to 80% of advanced stage ovarian cancers will develop resistance to the drug. The proposed studies will investigate the role of changes in nuclear pore architecture and patterning that may contribute to the acquisition of drug resistance by ovarian cancer cells.