THE ROLE OF PROTEIN KINASE C IN ENDOMETRIAL CANCER

蛋白激酶 C 在子宫内膜癌中的作用

• 批准号: 6871315
• 负责人: ANDREW P BRADFORD
• 金额: $ 31.35万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6871315
• 关键词: SDS polyacrylamide gel electrophoresis; apoptosis; athymic mouse; autoradiography; cell proliferation; endometrium; enzyme activity; enzyme inhibitors; etoposide; flow cytometry; neoplastic process; paclitaxel; protein isoforms; protein kinase C; protein localization; terminal nick end labeling; uterus neoplasms; xenotransplantation

DESCRIPTION (provided by applicant): Endometrial cancer is the most common gynecologic malignancy in developed countries, with approximately 39,000 new diagnoses and over 6000 deaths occurring annually in the United States. However, despite the evident risks to women's health, the molecular mechanisms underlying the onset and progression of endometrial tumors are poorly understood. Apoptosis, or programmed cell death, occurs during normal growth and development and in a variety of diseased states. Aberrant apoptosis is thought to contribute to the pathology, onset and progression of cancer and is associated with resistance to chemotherapy. In the endometrium, alterations in apoptosis have been implicated in both abnormal ovarian/menstrual cycling and endometrial hyperplasia and carcinoma. Increasing apoptotic index correlates with disease progression from atypia to malignancy and high levels of apoptosis are associated with more aggressive, higher-grade tumors with poorer patient prognosis. Endometrial cancers also exhibit alterations in the expression profile or activities of members of the Protein Kinase C (PKC) family, compared to normal tissue and aberrant levels or activation of specific PKC isoforms are postulated to contribute to endometrial neoplasia and transformation. Since PKCs are important regulators of both cell growth and apoptosis in many cell types, we hypothesize that these two characteristic of endometrial tumors are mechanistically linked and that select PKC isoforms differentially regulate apoptosis, survival and proliferation in the endometrium and are critical factors in the formation and progression of endometrial cancers. Adenoviral constructs encoding active or inhibitory PKC isoforms will be used to determine the functional role of specific PKCs in the regulation of apoptosis, growth, migration and invasion in endometrial cancer cells. Changes in PKC expression, localization and/or activity, induced by apoptosis, will be examined and potential upstream regulators or downstream targets of PKC in the apoptotic pathway identified and characterized. Finally, stable cell lines constitutively or inducibly expressing PKC constructs will be used in a mouse xenograft model to elucidate the functional role of PKC isoforms in the growth or regression of endometrial tumors in vivo. Understanding the function and molecular targets of specific PKCs in endometrial cancer will demonstrate their potential as prognostic or diagnostic indicators to identify aggressive, malignant, metastatic tumors and may provide novel strategies for therapeutic intervention.

描述（由申请人提供）：子宫内膜癌是发达国家中最常见的妇科恶性肿瘤，每年在美国大约有39,000个新诊断，每年有6000多人死亡。然而，尽管对妇女健康有明显的风险，但对子宫内膜肿瘤开始和进展的分子机制知之甚少。凋亡或程序性细胞死亡发生在正常生长和发育期间以及各种患病状态。异常细胞凋亡被认为有助于癌症的病理，发作和进展，并且与化学疗法的耐药性有关。在子宫内膜中，凋亡的改变与异常的卵巢/月经循环以及子宫内膜增生和癌有关。凋亡指数的增加与疾病从非典型性到恶性肿瘤的进展相关，而高水平的凋亡与更具侵略性的高级肿瘤有关，患者预后较差。与正常组织相比，子宫内膜癌还表现出蛋白激酶C（PKC）家族成员的表达谱或活性发生变化，或者假定特定PKC同工型的激活有助于子宫内膜肿瘤和转化。由于PKC是许多细胞类型中细胞生长和凋亡的重要调节剂，因此我们假设子宫内膜肿瘤的这两个特征是机械上关联的，并且选择PKC同工型差异地调节了子宫内膜的凋亡，存活和增殖，并且是子宫内膜癌的形成和进展的关键因素。编码活性或抑制性PKC同工型的腺病毒构建体将用于确定特定PKC在子宫内膜癌细胞中细胞凋亡，生长，迁移和侵袭中的功能作用。将检查由凋亡引起的PKC表达，定位和/或活性的变化，并在识别和表征的凋亡途径中的潜在上游调节剂或PKC的下游靶标。最后，在小鼠异种移植模型中将使用稳定的细胞系或诱导表达的PKC构建体来阐明PKC同工型在体内子宫内膜肿瘤的生长或回归中的功能作用。了解特定PKC在子宫内膜癌中的功能和分子靶标将证明其作为预后或诊断指标的潜力，以鉴定侵袭性，恶性，转移性肿瘤，并可能为治疗干预提供新的策略。