Advisory Committee Chair
Trygve O Tollefsbol
Advisory Committee Members
Ada Elgavish
Vithal Ghanta
Hui-Chen Hsu
Thane Wibbels
Document Type
Dissertation
Date of Award
2007
Degree Name by School
Doctor of Philosophy (PhD) College of Arts and Sciences
Abstract
Human chromosomes are protected from degradation associated with cell division by hexameric repeats of 5’-TTAGGG-3’ termed telomeres. During cellular replication human chromosomes undergo the loss of up to 300 bp of DNA with each division, reaching a critical length which leads to senescence and apoptosis. Most cancer cells bypass this lifespan regulatory mechanism by the expression of telomerase, a protein complex that adds telomeres through the reverse transcriptase activity of its catalytic subunit, hTERT. Approximatly 90% of all cancers express the hTERT gene making it an attractive target for novel cancer therapies. The objective of this dissertation was to help identify the mechanism by which (-)-epigallocatechin-3-gallate (EGCG), the major polyphenol found in green tea, can inhibit cancer cell growth and proliferation both in vitro and in vivo. Major discoveries of this work include: 1) exposure to EGCG leads to reduced cellular proliferation and an induction of apoptosis in MCF-7 breast cancer cells and HL60 promyelocytic leukemia cells; 2) EGCG treatment leads to hTERT down-regulation in MCF-7 cells but not in HL60 cells; 3) the ability of EGCG to reduce HL60 growth may not be due to epigenetic mechanisms; 4) MCF-7 cells grown in the presence of EGCG showed a time-dependent demethylation of the key E2F-1 binding sites in the hTERT promoter and an increased capacity to bind E2F-1; and 5) histone acetylation at the hTERT promoter region was decreased in MCF-7 cells. Additional studies preformed on human lung cancer xenografts revealed that intraperitoneal (i.p.) injection of EGCG can decrease methylation at the hTERT promoter in these tumors. EGCG was also shown to inhibit DNMT1 protein expression in treated tumor iii samples. Future studies further illustrating the epigenetic and genetic mechanisms involved in the anti-cancer mechanisms of EGCG in vivo are needed. Investigation into histone alterations after xenograft treatment is essential to understanding the epigenetic processes associated with EGCG treatment. In conclusion, EGCG has been shown to be an attractive natural compound with the ability to induce genetic and epigenetic pathways to both inhibit cancer cell proliferation and actively kill cancer cells by inducing apoptosis.
Recommended Citation
Berletch, Joel Bradford, "Green Tea Polyphenols Are Associated With Changes In Genetic And Epigenetic Anti-Cancer Mechanisms In Vitro And In Vivo" (2007). All ETDs from UAB. 3666.
https://digitalcommons.library.uab.edu/etd-collection/3666