Publication Date
2018
Document Type
Thesis
Committee Members
Kwang-jin Cho (Advisor), Madhavi Kadakia (Committee Member), Weiwen Long (Committee Member)
Degree Name
Master of Science (MS)
Abstract
Ras proteins are small GTPases that regulate cell growth, differentiation and apoptosis. There are three main isoforms: H-, N-, and K-Ras in mammalian cells, and they cycle between an active GTP- and inactive GDP-bound states. Constitutively active Ras mutations are found in ~15% of all human cancers. Of those, oncogenic K-Ras is found in ~98% of pancreatic, ~52% colorectal, and ~32% of lung cancers. In nearly 30 years since its discovery, there are no anti-K-Ras drugs currently available for clinical use. Since K-Ras must be localized to the plasma membrane (PM) for its full biological activity, targeting K-Ras PM interaction is a valid therapeutic approach for blocking its oncogenic activity. Our study identifies that avicin, a family of natural plant-derived triterpenoid saponins from Acacia victoriae, could be an anti-K-Ras-specific cancer drug. Avicin mislocalizes K-Ras from the PM to lysosomes and endomembranes, blocks its downstream signaling and reduces proliferation of K-Ras-addicted cancer cells. In addition, avicin redistributes phosphatidylserine (PS) from the inner-leaflet of the PM. We further identified that avicin mislocalizes K-Ras and PS from the PM through inhibiting sphingomyelinases (SMases), enzymes that hydrolyze of sphingomyelin (SM) to ceramide (Cer). Avicin increases cellular SM levels by disrupting SMase activity, their cellular localization and expression level. Furthermore, supplementation with exogenous Cer returns K-Ras and PS to the PM, suggesting cellular balance of SM and Cer is important for K-Ras and PS interaction with the PM. Taken together, we have identified that avicin is a new potent SMase inhibitor and an anti-K-Ras drug, and that targeting cellular SM/Cer balance could be a good starting point to develop anti-K-Ras cancer drugs.
Page Count
81
Department or Program
Department of Biochemistry and Molecular Biology
Year Degree Awarded
2018
Copyright
Copyright 2018, all rights reserved. My ETD will be available under the "Fair Use" terms of copyright law.
