Nuclear Pore Complex Architecture and Drug Resistance in Ovarian Carcinomas

卵巢癌的核孔复合体结构和耐药性

• 批准号: 7990123
• 负责人: DONALD STAVE KOHTZ
• 金额: $ 8.48万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7990123
• 关键词: Address; Affect; Architecture; Biology; Cancer Etiology; Carboplatin; Cell Count; Cell Nucleus; Cells; Cessation of life; Chromatin; Cisplatin; Complex; Data; Drug resistance; Epigenetic Process; Funding Opportunities; Geography; Grant; Investigation; Karyopherins; Malignant Epithelial Cell; Malignant neoplasm of ovary; Manuscripts; NUP214 gene; Nuclear Pore; Nuclear Pore Complex; Nuclear Pore Complex Proteins; Ovarian; Ovarian Carcinoma; Pattern; Pharmaceutical Preparations; Platinum; Population; Prevalence; Regulation; Relapse; Research; Research Project Grants; Resected; Resistance; Resistance development; Role; Science; Signal Pathway; Signal Transduction; Sorting - Cell Movement; Staging; Therapeutic; Tumor Tissue; Vertebrates; Woman; Women' s Health; Work; Yeasts; cancer cell; cell type; improved; neoplastic cell; novel; novel strategies; nuclear pore protein p62; outcome forecast; ovarian neoplasm; prognostic; public health relevance; response; small molecule; therapeutic effectiveness; tumor

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.

描述（由申请人提供）：虽然卵巢癌最初对使用铂药的治疗做出很好的反应，但大多数复发和获得抗药性。 在卵巢癌中，我们观察到卵巢癌切除的肿瘤组织中NUP62的减少，以及在核孔复合物（NPC）的亚核场中NUP62的重新分布。 此外，富含NUP62的NPC富集使卵巢癌细胞在培养中具有抗体素的抗性细胞。 研究表明，肿瘤细胞可以利用NUP62-和/或NUP214+ NPC富集所带来的存活优势。 为了推进这一假设，我们建议：1）研究NUP62和NUP214在卵巢癌中的积累和分布的改变，并破译这些因子如何对应于肿瘤参数；并且，为了研究NUP62或NUP214的表达或积累的变化如何影响其他核孔蛋白在NPC中的分布。 2）研究NUP62的敲低如何赋予对顺铂的抗性；具体而言，要解读NUP62+/NUP214-和NUP62-/NUP214+ NPC种群如何改变NUP62+/NUP214-和NPC种群如何通过NF-：B信号传导途径影响生存信号传导。 拟议的研究影响了表观遗传调节的基本生物学，也可能阐明一种新方法来改善用铂药治疗的卵巢癌的预后。 随着NPC种群的模式和结构会影响卵巢癌细胞对顺铂的敏感性，可以开发出小分子，从而改变NPC结构以增强其治疗有效性。这些药物可用于减少对治疗后生存和/或变得潜在的细胞数量，也可以将获得铂耐药性的复发性肿瘤化学敏感性。 公共卫生相关性： 拟议的研究涉及一种新型机制，卵巢瘤细胞获得了对顺铂的抗性。 虽然卵巢肿瘤最初对顺铂和卡铂的反应良好，但有70％至80％的晚期卵巢癌将产生对药物的抗性。 拟议的研究将研究核孔结构变化和模式的变化，这可能有助于从卵巢癌细胞获得耐药性。