2009-08-012024-05-17https://scholars.lib.ntu.edu.tw/handle/123456789/683025摘要：乳癌是目前全球最普遍的女性癌症，美國每年有超過20萬名婦女被診斷出乳癌，其中有4萬1千人因而死亡，因此有效的標靶治療變成非常重要的癌症治療研究主題之一。我們最近的研究成果發現，ATP合成&#37238;在癌化組織中會高度表現且出現在乳癌細胞表面的量比在正長細胞多， 其抑制劑會毒殺乳癌細胞，但對正常細胞卻無影響；此外，我們也發現ATP合成&#37238;抑制劑會誘導細胞凋亡並導致細胞週期停止於G0/G1期。本研究成果刊登於Journal of Proteome Research (2008)並獲選為美國化學會及科學今日的熱門新聞，該報導指出我們首次發現阻斷能量供應蛋白質能殺死癌細胞，且ATP合成&#37238;可能是新穎的抗乳癌藥物標靶。本計畫的主要目標是要探討以ATP合成&#37238;抑制劑為主的抗乳癌標靶治療及其作用的分子機制。 特定的目標： 1. 測量ATP合成&#37238;抑制劑在乳癌細胞的抑制效果。 2. 研究ATP合成&#37238;如何從粒線體移動到乳癌細胞膜上的機制。 3. 解析ATP合成&#37238;抑制劑所調控的癌細胞生長抑制及死亡的分子作用機制。 本計畫著重於發展乳癌的標靶治療，藉由探討ATP合成&#37238;抑制劑作用於乳癌細胞的分子機制，開發出有潛力的抗乳癌藥物。ATP合成&#37238;抑制劑在未來可於醫療用途上做測試，或許能提供更新更有效的抗癌療程。 <br> Abstract: Breast cancer is the most common malignancy among women in developed regions of the world. In the United States, more than 200,000 women are diagnosed with breast cancer each year and nearly 41,000 patients die of the disease. The investigation of effective targets has therefore been one of the most important research topics in cancer therapy. Targeting tumor tissues is one of the most powerful approaches to accelerate the efficiency of anticancer treatments. The investigation of effective targets, including proteins specifically and abundantly expressed in abnormal regions, has been one of the most important research topics in cancer therapy. Recently, we have applied systems biology approach on drug discovery for breast cancer and the results suggest that ATP synthase may represent a new target for fighting breast cancer. The finding has been published in Journal of Proteome Research (2008) and was selected as a press release entitled “First evidence that blocking key energy protein kills cancer cells” by American Chemical Society as well as reported in Science Daily. In our preliminary studies, we treated the breast cancer cells with an ATP synthase inhibitors and observed strong inhibition on the proliferation of several breast cancer cell lines but little influence on the normal cell line. We found that ATP synthase inhibitors inhibit proliferation of breast cancer cells by inducing apoptosis and arresting cell cycle at the G0/G1 phase. In addition, we found ATP synthase can be expressed on tumor cell surface more than on normal cell surface. These results stimulate us to study how ATP synthase move from mitochondria to cancer cell surface and the mechanism of ATP synthase inhibitors on cell death. The major objective of this proposal is to study the targeting therapy for breast cancer by ATP synthase inhibitors and their related molecular mechanism. The specific aims are (i) To measure the inhibitory effects on tumor metastasis by ATP synthase inhibitors in breast cancer cells. (ii) To study how ATP synthases move from mitochondria to cell surface on breast cancer cells. (iii) To elucidate the underlying molecular mechanism of ATP synthase inhibitor-mediated breast cancer cell growth inhibition and, ultimately, apoptosis. With the proposed study, we might be able to elucidate the effect of ATP synthase inhibitors on cancer cells and understand more about their regulatory molecular mechanism in cancer cell apoptosis. Furthermore, the information will provide a valuable in-depth insight in targeted cancer therapy.ATP 合成&#37238抑制劑乳癌細胞凋亡分子機制癌症治療ATP synthase inhibitorbreast cancerapoptosismolecular mechanismcancer therapy