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: 6712616
• 负责人: ANDREW P BRADFORD
• 金额: $ 31.52万
• 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/6712616
• 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最常见的妇科恶性肿瘤，在美国每年约有 39,000 例新诊断病例和超过 6000 例死亡病例。然而，尽管对女性健康存在明显的风险，但子宫内膜肿瘤发生和进展的分子机制却知之甚少。细胞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疾病状态下。异常的细胞凋亡被认为会导致癌症的病理、发病和进展，并与化疗耐药相关。在子宫内膜中，细胞凋亡的改变与卵巢/月经周期异常以及子宫内膜增生和癌有关。细胞凋亡指数的增加与从异型性到恶性肿瘤的疾病进展相关，高水平的细胞凋亡与更具侵袭性、更高级别的肿瘤以及较差的患者预后相关。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的改变，并且推测特定 PKC 同种型的异常水平或激活有助于子宫内膜瘤形成和转化。由于 PKC 是许多细胞类型中细胞生长和凋亡的重要调节因子，我们假设子宫内膜肿瘤的这两个特征在机制上是相关的，并且选择 PKC 亚型差异调节子宫内膜的凋亡、存活和增殖，并且是子宫内膜肿瘤形成的关键因素。和子宫内膜癌的进展。编码活性或抑制性 PKC 亚型的腺病毒构建体将用于确定特定 PKC 在调节子宫内膜癌细胞凋亡、生长、迁移和侵袭中的功能作用。将检查由细胞凋亡诱导的 PKC 表达、定位和/或活性的变化，并鉴定和表征细胞凋亡途径中 PKC 的潜在上游调节剂或下游靶标。最后，组成型或诱导型表达 PKC 构建体的稳定细胞系将用于小鼠异种移植模型，以阐明 PKC 亚型在体内子宫内膜肿瘤生长或消退中的功能作用。了解子宫内膜癌中特定 PKC 的功能和分子靶点将证明它们作为预后或诊断指标的潜力，以识别侵袭性、恶性、转移性肿瘤，并可能为治疗干预提供新策略。