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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

these cells could be due

these cells could be due to an overall increase in generation time because retinol does decrease cell growth (Figure 2.1B). The differing responses between the HCT-116 cell line and the other three may reflect the heterogenicity of these cell lines, tumor stage (carcinoma versus adenoma), and presence or absence of various proteins in each cell line, for example APC (adenomatous polyposis coli) or p53. Retinoids tend to induce cell cycle arrest by blocking the G1 to S phase transition [for review see: (30)]. Unfortunately, the effect of retinoids on cell cycle regulatory proteins appears to be cell type specific (30). For example, in carcinogen-exposed immortalized human bronchial epithelial cells, ATRA-induced G1 arrest is associated with decreased cyclin D1 protein levels due to ubiquitin-mediated degradation of cyclin D1 (68,69). In contrast, ATRA-induced G1 arrest in MCF-7 breast cancer cells is associated with decreased pRB phosphorylation, while cyclin D1, p21 WAF1/CIP1 , cdk4 and cdk6 activity either does not change or decreases slightly, depending on the study (70- 72). This study shows that retinol is acting independent of the RAR to inhibit colon cancer cell growth. Previously, retinoids have been shown to exert their receptor- independent effects via interactions with protein kinase C alpha (PKCα) (73), F-actin (74), c-Raf kinase (62), regulating mitochondrial membrane potential (75), generating reactive oxygen species (76), increasing intracellular ceramide levels (77), activating c- Jun N-terminal kinase (78), inducing ubiquitin-dependent proteolysis (68,69), and affecting MAP kinase (79,80), phosphatidylinositol 3-kinase (PI3K)/Akt (81), and epidermal growth factor receptor (EGFR) signaling (82). The Hammerling lab has shown that the retroretinoids, retinol, and ATRA can bind PKCα and affect its redox 29

activation (73). In contrast to our present study, they speculate that retinol antagonizes AR and increases cell survival by binding to c-Raf and augmenting its response to reactive oxygen species generated during UV irradiation, however the link between cell growth and c-Raf activation was not directly examined (62). Because AR induces apoptosis we do not expect retinol to be affecting cell growth by interacting with c-Raf or any of the other pathways listed above that induce apoptosis. In conclusion, this study shows that retinol acts through a novel mechanism to inhibit the growth of both ATRA-sensitive and ATRA-resistant colon cancer cells by affecting cell cycle progression. Resistance to ATRA is a common phenomenon and limits the use of RA-derivatives as chemotherapy. We speculate that retinol, or a derivative of it, may prove an effective therapy to treat colorectal cancer. ACKNOWLEDGEMENTS The authors would like to thank Dr. Lorraine Gudas for the gift of the 4- oxoretinol standards, Dr. Ulrich Hammerling for providing the AR standard, Dr. Dianne Soprano for the pRARE-CAT construct, and Dr. Rosh Chandraratna for the RAR-pan antagonist, AGN 193109. 30

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