| Title | The role of P21 in antagonizing apoptosis and causing senescence in response to gallotannin in human colon cancer cells / by Hind Camille Zahr | Thesis |
| Name(s) | Zahr, Hind Camille (Main Author)
American University of Beirut. Faculty of Arts and Sciences. Department of Biology (Related name)
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| Publication | 2009
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| Link(s) | Click for full-text
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| Physical Details | xviii, 86 leaves; ill.; 30 cm.
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| Subjects | Colon (Anatomy)--Cancer
Cancer cells
Cancer--Prevention
Apoptosis--Therapeutic use
Plant extracts
Cells--Aging
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| Classmarks | T:005302
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| Notes | Dissertation: Thesis (M.S.)--American University of Beirut, Dept. of Biology, 2009.
Dissertation: Advisor : Dr. Hala Gali-Muhtasib, Professor , Biology
Member of Committee : Dr. Colin Smith, Associate Professor, Biology
Member of Committee : Dr. Aida Abdul Karim Habib, Professor, Biochemistry.
Bib. & Index: Bibliography : leaves 71-86.
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| Abstract | Gallotannin (GT) is a polyphenol that is active against colon cancer. GT has been shown to induce cell cycle arrest in the human colon cancer cell line HCT116 and apoptosis in the isogenic cell line HCT116 p21-/-. The mechanisms underlying these anti-carcinogenic effects are not well defined. The aim of this study is to elucidate the molecular mechanisms of action of GT, to determine whether GT causes DNA damage, to determine the role of p21 in antagonizing apoptosis and causing senescence in HCT116 human colon cancer cells and to determine the molecular mechanisms involved in the antitumorigenic effects of GT in vivo.
This work shows that GT causes DNA damage and decreases the survival of HCT116 cells. GT downregulated Mdm2 and upregulated p53 expression levels in wild type HCT116 cells. Conversely, GT upregulated Mdm2 and downregulated p53 expression levels in HCT p21-/- cells. It also downregulated E2F-1 protein expression levels in wild type HCT116 cells and upregulated it in HCT p21-/- cells. GT induced transient upregulation of p21 at 20 microg/ml followed by remarkable reduction at 40 microg/ml in wild type HCT116 cells. GT-induced apoptosis in HCT116 p21-/- cells correlated to decreased p53 and Puma. Transfection of HCT116 p21-/- cells with p21 plasmid rescued the cells from apoptosis and restored wild type phenotype upon GT treatment. Moreover, GT induced senescence in wild type HCT116 cells but not in HCT116 p21-/- cells.
Previous work in this laboratory has shown that GT decreases and stabilizes the growth of human colon cancer xenografts in NOD/SCID mice. In an attempt to investigate the mechanism of in vivo growth inhibition, tumor tissues were stained for Ki-67, VEGFA, MMP-2, and MMP-9. GT decreased the expression of Ki-67, a proliferation marker, VEGFA, an angiogenesis marker, and MMP-2, a metastasis marker in the NOD/SCID xenograft model of colon cancer. GT had no effect on the expression levels of MMP-9 protein.
In conclusion, the presence of p21gene modulates the response of HCT116 cells to GT. When p21 is present, senescence is induced while in p21 absence higher proportion of cells die by apoptosis. The senescence inducing property of GT in HCT116 cells supports its development for use in anti cancer therapy.
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Category | | | Jafet Archives and Special Collections | Thesis | T:5302:c.1 | ASC-Binding | Building Use |
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