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Studying the Mechanism of Ferroptosis Induced by a Novel Class of Small Molecules

Alqahtani, Hanan Dhafer S
http://rave.ohiolink.edu/etdc/view?acc_num=toledo1470398949

Abstract Details

2016, Master of Science, University of Toledo, Biology (Cell-Molecular Biology).
Cancer is a group of diseases characterized by abnormal features including continuous abnormal growth, uncontrolled cell division, and the ability to spread, invade and destroy surrounding tissues and organs in the body. It is the second most common cause of death in the USA. Therefore, discovering strategies, signaling pathways, and targeted molecules to eliminate cancer cells has been intensively investigated. Cells in multicellular organisms undergo death for many reasons such as senescence and external chemical stimulus. There are many forms of cell death including necrosis, apoptosis, and autophagy, and each form is morphologically, biochemically, and genetically distinct. In addition, each form is activated differently from each other. We are investigating a recently described form of cell death called Ferrptosis that was originally observed in response to the small molecule called Erastin. We hypothesize that Ferroptosis can be exploited to eliminate certain types of tumor cells. In ferroptosis, an iron-dependent form of nonapoptotic cell death, cells die due to the iron-dependent accumulation of Reactive Oxygen Species (ROS). ROS are chemically reactive molecules than contain oxygen, and they are formed naturally as a byproduct of the metabolism of oxygen. We identified a small molecule called 6E that can kill number of cancer cell lines by Ferroptosis. There are many cellular factors that increase the sensitivity of the cells to be killed by 6E such as activated RAS/MAPK pathway, presence of p53 alleles, iron metal, loss of the epithelial gene E-cadherin, and expressing vimentin the mesenchymal gene. In this thesis we study the mechanism of ferroptosis induced by 6E and related compounds. We tested a number of different cancer cell lines toward 6E. Also we measured the level of glutathione inside the cells, and the level of secreted glutamate after 6E treatment. Also, we tested the effect of the iron chelator CPO and the antioxidant trolox in cell death induced by 6E. Together these experiments suggest that 6E induces ferroptosis by inhibiting XC-, a transport that brings cystine into the cell required to replenish the antioxidant glutathione. We also show that mesenchymal cells are particular sensitive to the 6E precursor molecule. Consistent with these, we find that a number of childhood cancer cell lines derived from mesenchymal tissues are sensitive to 6E.
William Taylor (Advisor)
Lirim Shemshedini (Committee Member)
Heather Conti (Committee Member)
L.M. Viranga Tillekeratne (Committee Member)
100 p.
Biology

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Citations

  • Alqahtani, H. D. S. (2016). Studying the Mechanism of Ferroptosis Induced by a Novel Class of Small Molecules [Master's thesis, University of Toledo]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1470398949

    APA Style (7th edition)

  • Alqahtani, Hanan. Studying the Mechanism of Ferroptosis Induced by a Novel Class of Small Molecules. 2016. University of Toledo, Master's thesis. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=toledo1470398949.

    MLA Style (8th edition)

  • Alqahtani, Hanan. "Studying the Mechanism of Ferroptosis Induced by a Novel Class of Small Molecules." Master's thesis, University of Toledo, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1470398949

    Chicago Manual of Style (17th edition)

toledo1470398949
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This open access ETD is published by University of Toledo and OhioLINK.