| Summary: | 碩士 === 中國醫藥大學 === 癌症生物學研究所碩士班 === 102 === Breast cancer is one of the ten leading causes of cancer-related death among women worldwide including Taiwan. Accumulating evidence shows that microenvironment around tumors consisting of many cell types, such as endothelial cells, fibroblasts and inflammatory cells, plays an important role in tumor progression. TNF-alpha secreted by tumor-associated inflammatory cells is a primary pro-inflammatory cytokine and plays a critical role in many cancers. Our group previously has identified a novel inflammation-mediated tumor angiogenesis via IKK beta-TSC1-mTOR pathway. Thus, we herein try to find novel inhibitors blocking IKK beta interaction with TSC1 and their downstream mTOR pathway, thereby inhibiting tumorigenesis. We initiated our studies by using high-throughput screening (HTS) of compounds library, and then used Western Blotting analysis to further characterize the hit compounds. The Western Blotting results showed that some of the hit compounds could inhibit TNF-alpha-induced mTOR activation by examining the phosphorylation status of S6K1 and IKK-beta, but didn’t affect total protein expression level of S6K1 and IKK-beta in breast cancer cells. The immunoprecipiation assays and GST pull-down assays indicate that compounds 12 and 17 could inhibit IKK-beta interaction with TSC1. Moreover, compounds 12 and 17 also inhibit cell proliferation, migration and tube formation ability of HUVEC cells. These finding clearly suggest that compounds 12 and 17 inhibit IKK beta-TSC1-mTOR pathway. We will further investigate the effects of these hit compounds on tumor angiogenesis in animal models in vivo, and hopefully develop the novel drugs for cancer therapy in the future.
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