CALCIUM SIGNALING AND OVARIAN CANCER

钙信号传导与卵巢癌

• 批准号: 6174069
• 负责人: Karin D Rodland
• 金额: $ 28.33万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-01 至 2002-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6174069
• 关键词: calcium binding protein; calcium flux; cell proliferation; clinical research; enzyme activity; female; gene induction /repression; human genetic material tag; human subject; mitogen activated protein kinase; neoplasm /cancer genetics; ovary neoplasms; phosphatidylinositol 3 kinase; protein structure function; protooncogene; tissue /cell culture

Ovarian carcinoma is one of the leading causes of cancer death among women. The low survival for victims of ovarian cancer (less than 13 percent for stage III disease) reflect, in large part, the highly aggressive and metastatic character of ovarian adenocarcinomas. Despite the obvious seriousness of ovarian cancer, very little is known about the normal biology of the ovarian surface epithelial cells which give rise to the most malignant forms of ovarian carcinoma. Data presented in this proposal indicate that increased extracellular calcium exerts a significant proliferative effect on ovarian surface epithelial cells, as measured by both thymidine incorporation and cell growth curves. Ovarian surface epithelial cells express mRNA and protein for the recently cloned Calcium-sensing Receptor (CaR). This G-protein coupled receptor has been shown to be responsible for triggering parathormone release from parathyroid cells in response to elevated extracellular calcium. We have shown that the CaR in ovarian surface epithelial cells displays the same functional responses to extracellular calcium and other agonists (including gadolinium) as does the parathyroid CaR. Activation of the CaR in ovarian surface epithelial cells is associated with increases in tyrosine phosphorylation, increased activity of the mitogen-activated kinase ERK2, and increased src kinase activity. Expressing a non-functional mutant of the CaR (R796W) inhibited the increases in tyrosine phosphorylation and ERK2 activity observed in response to agonists of the CaR, indicating that the presence of functional CaR is required for these responses to increased extracellular calcium. Furthermore, we have observed that two of four ovarian tumor cell lines examined appear to over-express CaR mRNA, as well as expressing a novel CaR transcript. These ovarian tumor cell lines are no longer growth-inhibited in low calcium media. This proposal is based on the hypotheses that signal transduction downstream of the CaR leads directly to activation of ERK kinase and increased proliferation, and that disruption of normal CaR expression and/or function contributes to the loss of normal growth controls in ovarian carcinogenesis. These hypotheses will be tested by 1) disrupting known signaling mechanisms and observing the effect on CaR-dependent activation of src and/or ERK2, using transfection of dominant negative mutants or selective chemical inhibitors, 2) using a prospective study of CaR expression in patients with ovarian cancer to test clinical relevance.

卵巢癌是癌症死亡的主要原因之一