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Copyright by Eunyoung Park 2007 - The University of Texas at Austin

Copyright by Eunyoung Park 2007 - The University of Texas at Austin

acid (9-cis-RA), and

acid (9-cis-RA), and 4-(hydroxyphenyl)retinamide (4-HPR) can inhibit the formation of carcinogen-induced aberrant crypt foci, a precursor to colon cancer, as well as colon tumors in rats (45-48). Retinyl palmitate was recently shown to inhibit high fat diet- induced aberrant crypt foci (45). In addition, several in vitro studies illustrate that retinoids have potent antiproliferative effects on colon cancer cell lines and may hold potential for both chemoprevention and chemotherapy of colon cancer. Taken together, it is more relevant to examine the effects of retinol on colon cancer cell growth and metastasis because (1) colonocytes are primarily exposed to retinol, (2) liver is the major storage site of retinol and colon cancer metastasis site, and (3) ATRA resistance is common in colon carcinomas. This dissertation focuses on the study of retinol as an inhibitor of ATRA-resistant human colon cancer cell line growth and metastasis in vitro and in vivo. Chapter 1 introduces background information concerning colorectal cancer progression and the role of retinol as a chemotherapy agent for colon cancer. Chapter 2 will focus on the initial studies showing the mechanism of growth inhibition in ATRA-resistance colon cancer cells by retinol treatment independent of ATRA/RAR/RARE signaling. Chapters 3 and 4 are concerned with the ability of retinol to inhibit colon cancer cell invasion by decreasing MMP-2 and -9 activity as well as PI3K activity, respectively. Chapter 5 will focus on the ability of dietary vitamin A supplementation to inhibit the liver metastasis of colon tumors in a nude mouse xenograft model. Chapter 6 will summarize the findings of these studies and propose future directions to continue to understand the molecular mechanisms by which retinol inhibits the growth and metastasis of ATRA-resistant human colon cancer cell lines. 9

FIGURE 1.1. GENETIC ALTERATIONS ASSOCIATED WITH COLON CARCINOGENESIS. Mutation in APC, K-ras, DCC and p53 transform normal colon epithelium to metastatic colon cancer (49). 10

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