柚皮素调控乳腺癌细胞TGF-β1分泌的机制研究

项目名称： 柚皮素调控乳腺癌细胞TGF-β1分泌的机制研究

项目编号： No.81503106

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 张发云

作者单位： 中国科学院生物物理研究所

项目金额： 17.9万元

中文摘要： 乳腺癌的转移是造成乳腺癌患者死亡的主要原因。研究表明，TGF-β1水平的异常升高与乳腺癌的恶性转移紧密相关，开发TGF-β1信号通路抑制剂为治疗乳腺癌的转移提供了新思路。然而，现有的抗体类药物或受体抑制剂对TGF-β1的全身性抑制导致许多不良毒副作用。临床上亟待开发毒性小、选择性强的对抗TGF-β1的新型药物。我们发现，小分子化合物柚皮素能下调乳腺癌接种小鼠体内异常增加的TGF-β1水平，显著抑制其肺脏转移。和现有的TGF-β1抑制剂不同，柚皮素选择性地阻止了乳腺癌细胞内TGF-β1向胞外的分泌而不影响其转录和蛋白表达。鉴于TGF-β1蛋白的分泌受多个转运环节的严格调控，本课题拟在胞内转运的不同调控环节上系统地研究柚皮素对乳腺癌细胞TGF-β1分泌的作用机制。柚皮素调控TGF-β1分泌机制的阐明将不仅为柚皮素的新药开发提供理论依据，而且使调控蛋白的胞内转运成为可能，为药物研发提供新的思路。

中文关键词： 乳腺癌转移；转化生长因子β1；柚皮素；分泌调控

英文摘要： The metastasis of breast cancer cells accounts for the leading cause of cancer deaths in patients. It is reported that the raise of TGF-β1 in vivo is closely related with malignant metastasis. The development of TGF-β1 signaling inhibitors provides new sight for breast cancer metastasis therapy. However, overall blockage of TGF-β1 signaling by receptor inhibitors or antibodies brings serious adverse effects. In clinic, there is an urgent need for exploring of new inhibitors with low system toxicity and specificity to TGF-β1. We previously found that naringenin, a low molecular weight compound, showed significantly inhibition of breast cancer metastasis through down-regulation of TGF-β1 level in breast cancer. Differing to the existed TGF-β1 inhibitors, naringenin selectively blocked the secretion of TGF-β1 but showed no effects on its transcription and translation. As the secretion of TGF-β1 is regulated by multiple transporting steps, we propose to investigate the regulational mechanism of naringenin on different transporting steps of TGF-β1 in breast cancer cells. The demonstration of regulational machenism on TGF-β1 secretion by naringenin will provide the theoretical support for developing novel drugs, and make the regulation of protein transporting posibility.

英文关键词： breast cancer metastasis;TGF-β1;naringenin;secretory regulation