Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Pharmacology and Toxicology

Supervisor

John DiGuglielmo

Abstract

Cell migration is an important mediator of cancer metastasis and invasion, which is responsible for 90% of cancer-related premature deaths in Canada. Synthetic triterpenoids are a class of promising anti-cancer compounds that have shown considerable efficacy in targeting various cellular functions including apoptosis, growth, inflammation and cytoprotection in both cell culture and animal tumor models. However, their effect on cell migration, an important event in metastasis, remains poorly understood. This thesis focuses on deciphering the molecular mechanisms whereby the synthetic triterpenoids affect cell migration. I observed that the imidazolide and methyl ester derivatives of the synthetic triterpenoid, 2-cyano-3,12-dioxooleana-1,9-dien-28-oic aic acid (CDDO-Im and CDDO-Me), inhibit cell migration by disrupting microtubule dynamics. In addition, I found that these triterpenoids disrupt cell polarity by displacing proteins at the leading edge of migrating cells. Furthermore, using a two-pronged proteomic approach involving protein arrays and mass spectrometry, I identified numerous triterpenoid-binding targets involved in actin polymerization and focal adhesion maintenance. My data further revealed that triterpenoids inhibit branched actin polymerization by targeting Arp3 in the Arp2/3 complex and target GSK3b activity to alter focal adhesion sizes. Collectively, my studies provided novel insights on the underlying molecular mechanisms by which triterpenoids act to affect cell migration. This knowledge will be important for developing a more efficacious and specific therapeutic triterpenoid compound that targets cancer metastasis.


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Cell Biology Commons

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