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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

Chapter 6: Summary and

Chapter 6: Summary and Future Directions Colorectal cancer is the third most common cancer in the USA. Early diagnosis and treatment helps decrease the five year survival rate for patients with colorectal cancer. However, colorectal cancer is still the third leading cause of cancer death in the USA. Moreover, distant metastases of colon cancer are more problematic. These facts indicate that we need more effective treatment for colon cancer. In addition, many studies have been conducted to show that micronutrients reduce colon cancer incidence and progression. We focused on the effect of retinol on colon cancer progression because colonocytes are primarily exposed to retinol from the diet. Chapter 1 introduced the importance of inhibiting human colon cancer cell growth and metastasis. It also provided the reasons to study the effect of retinol on colon cancer growth and metastasis instead of other bioactive retinoids such as ATRA. Chapter 2 showed that retinol inhibited the growth of both ATRA-sensitive and ATRA-resistant human colon cancer cell lines independent of the ATRA/RAR/RARE retinoid signaling pathway. First, retinol was not metabolized to other bioactive retinoids, such as ATRA. Second, retinol did not activate RARE-mediated gene transcription. Finally, a RAR-antagonist blocked the ability of ATRA to inhibit the growth of ATRA-sensitive HCT-15 cells, as expected, but did not block the ability of retinol to inhibit the growth of any cell line examined. Therefore, even in the presence of functioning RAR, retinol did not inhibit cell growth by the actions of its metabolite ATRA, because this metabolite is not present in ATRA-sensitive HCT-15 cells. In addition, retinol acted through a novel mechanism to inhibit the growth of both ATRA- 117

sensitive and ATRA-resistant colon cancer cells by affecting cell cycle progression. In Chapter 2, retinol also decreased tumor cell growth by inducing G0/1 arrest in three of the cell lines examined. These results suggest future directions concerning the molecular mechanisms underlying retinol’s ability to arrest the cell cycle independent of RAR/RXR/RARE and inhibit cancer cell growth. Progression from G0/1 to S phase is mediated by cyclins D and E and cyclin dependent kinases (Cdk) 2, 4 and 6. Cyclin-Cdk complexes are influenced by several cell cycle regulatory proteins such as protein kinases and phosphatases that modify Cdks, the cyclin dependent kinase inhibitors (CKIs); p27, p21 and p16, and regulatory proteins such as p53 and E2F. Unfortunately, the effect of retinoids on cell cycle regulatory proteins appears to be cell type specific (30). For example, cyclin D1 was responsible for G1 arrest in carcinogen-exposed immortalized human bronchial epithelial cells (68,69). In contrast, decreased phosphorylation of pRB was the major factor for G0/1 arrest in MCF-7 breast cancer cells (70-72). We have seen that inhibition of invasion by retinol treatment depends on posttranslational modification such as phosphorylation events (Chapters 3 and 4). However, we have not examined the effect of cycloheximide (translation inhibitor) and actinomycin D (transcription inhibitor) on retinol’s inhibitory effect on cell growth due to toxicity of these chemicals when treating for more than 24 hr required for retinol to show its inhibitory effect on cancer cell growth. Therefore, the inhibitory effect of retinol on colon cancer cell growth is open to all three possibilities; (1) inhibiting mRNA or (2) protein synthesis or (3) inhibiting posttranslational modification. To examine possible candidates for cell cycle 118

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