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Avicin is a potent sphingomyelinase inhibitor that blocks K-Ras plasma membrane interaction and its oncogenic activity

Garrido, Christian M.
http://rave.ohiolink.edu/etdc/view?acc_num=wright1545974237243977

Abstract Details

2018, Master of Science (MS), Wright State University, Biochemistry and Molecular Biology.
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.
Kwang-jin Cho, Ph.D. (Advisor)
Madhavi Kadakia, Ph.D. (Committee Member)
Weiwen Long, Ph.D. (Committee Member)
81 p.
Biochemistry; Molecular Biology
Avicin; triterpenoid saponin; K-Ras; plasma membrane; phosphatidylserine; sphingomyelinase; sphingomyelin; ceramide; non-small cell lung cancer; pancreatic ductal adenocarinoma

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Citations

  • Garrido, C. M. (2018). Avicin is a potent sphingomyelinase inhibitor that blocks K-Ras plasma membrane interaction and its oncogenic activity [Master's thesis, Wright State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=wright1545974237243977

    APA Style (7th edition)

  • Garrido, Christian. Avicin is a potent sphingomyelinase inhibitor that blocks K-Ras plasma membrane interaction and its oncogenic activity. 2018. Wright State University, Master's thesis. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=wright1545974237243977.

    MLA Style (8th edition)

  • Garrido, Christian. "Avicin is a potent sphingomyelinase inhibitor that blocks K-Ras plasma membrane interaction and its oncogenic activity." Master's thesis, Wright State University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=wright1545974237243977

    Chicago Manual of Style (17th edition)

wright1545974237243977
156
© 2018, all rights reserved.
This open access ETD is published by Wright State University and OhioLINK.