| الوصف: |
Although cancer survival rates have significantly improved over the past few decades, the improvements are primarily due to early diagnosis and inhibiting cancer growth. Limited progress has been made in the treatment of cancer metastasis, which contributes to 90% of cancer related deaths, and therapeutic agents targeting the various aspects of metastasis are lacking. One potential approach is to utilize small pharmacological compounds to inhibit tumour cell motility, as a strategy against tumour cell migration, invasion, and metastasis. The acetylenic tricyclic bis-(cyano enone), TBE-31, has been shown to be a promising chemopreventative compound. However, its effects on cell migration are unknown. This thesis focuses on deciphering the molecular mechanisms TBE-31 utilizes to inhibit cell migration. I demonstrated that TBE-31 binds with cysteine 374 of actin, inhibits actin polymerization and stress fiber formation. These findings were applied to a model of epithelial-to-mesenchymal transition, a precursor event to metastasis, where I determined TBE-31 was able to inhibit the crucial rearrangement of cortical actin to form actin stress fibers, which prime tumour cells for migration. In addition to the actin cytoskeleton, I demonstrated that TBE-31 alters microtubule dynamics and organization. Microtubule-dependent trafficking was also shown to be disrupted by TBE-31, and the localization of the polarity proteins Rac1, IQGAP and Tiam1 were altered from the leading edge of migrating cells. Lastly, TBE-31 was shown to inhibit Rat2 and NIH3T3 fibroblast as well as H1299 non-small cell lung cancer tumour cell migration. Taken together, my work provides novel insights on the underlying mechanisms by which TBE-31 utilizes to inhibit cell migration and provide important knowledge for developing therapeutic compounds that target tumour cell motility in metastasis. |
