Honors Program

Honors in Biology

Date of Award

5-2011

Thesis Professor(s)

Sharon Campbell

Thesis Professor Department

Biochemistry and Molecular Biology

Thesis Reader(s)

Lev Yampolsky, Mark L. Giroux

Abstract

Colorectal cancer is the third most prominent cancer world-wide and it is the second leading cause of cancer deaths in the United States. Many dietary components affect the risk of developing colorectal cancer, such as Vitamin E. Of the eight isomers of Vitamin E, four have a tocotrienol structure. Tocotrienols are found at highest concentrations in palm oil, which is ingested more in areas of Asia where the incidence of colorectal cancer is the lowest, suggesting a role of tocotrienols in the prevention of colorectal cancer. The metabolism of Arachidonic acid pathway produces a host of pro-inflammatory metabolites either by the Cyclooxygenase (Cox) pathway or the Lipoxygenase (Lox) pathway. The expression of Lox is increased in various human cancer lines; this over expression has been associated with tumor cell proliferation, resistance to apoptosis, and angiogenesis. Another important pathway related to cancer involves mTOR (mammalian target of rapamycin), which is involved in cell growth and human tumorigenesis. The focus of this study included treatment of the HCT-116 colon cancer cell line with gamma tocotrienol to examine potential pathways involved in the induction of apoptosis. Also, whether the Vitamin E-mediated signaling through Arachidonic acid metabolism is necessary for the down regulation of protein translation in the mTOR pathway by using chemical inhibitors specific to Arachidonic acid in the presence and absence of vitamin E treatment was explored. The colon cancer cell line, HCT-116, was treated with gamma tocotrienol isomer and then isolated at 18 and 24 hours. Cells lysates were analyzed by Western Blotting. Our data shows that the mTOR pathway is downregulated by treatment with gamma tocotrienol at 18 hours and 14 hours for 5 µM demonstrating that protein translation is abrogated. Phospho S6 ribosomal protein and phospho-p70 S6 kinase are both downregulated, and phospho-4EBP1 is up regulated upon treatment of gamma tocotrienol. Furthermore, at the same concentrations, Caspase 12 and Caspase 8 are cleaved indicating apoptosis. In addition, parallel up-regulation of 15-LOX-1 and down regulation of Cox-2 at 5 µM at 18 hours is observed. Upon treatment with Caffeic acid, 15-lox-1 is over expressed causing mTOR trend to reverse and down regulation of ERK. Thus, mTOR regulation is dependent on a delicate balance of fatty acid metabolites.

Document Type

Honors Thesis - Open Access

Copyright

Copyright by the authors.

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