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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

metabolite, inhibits

metabolite, inhibits colon cancer cell invasion. It is possible that an unknown and undetected bioactive metabolite of retinol was formed that existed only briefly and was not identified in our previous study, however we have also previously shown that retinol cannot induce CAT-activity in cells transfected with a pRARE-CAT construct (95). In the present study, the inability of a pan-RAR antagonist to block the inhibitory effects of retinol on cell invasion (Fig. 3.2) supports our conclusion that retinol inhibits cell invasion by an ATRA and RAR-independent mechanism. Although the cell lines used in the present study either do not express RAR or express only some RAR (90,93,99) we used the RAR pan-antagonist, AGN 193109, to block any potential RAR activation in the current study and ensure that the effects of retinol on cell invasion would be exclusive of ATRA and RAR. AGN 193109 exhibits a high affinity for all RAR (100) and we have shown previously that AGN 193109 blocks the inhibitory effects of ATRA on ATRA-sensitive cell growth (95). Although a genetic approach would have been more specific, the dominant negative RAR construct available is activated by retinol (104), making it inappropriate for this study. The ability of MMPs to digest the ECM is regulated at the mRNA, protein, and, most importantly, enzyme activity level. The current study is the first, to our knowledge, to show that retinol inhibits colon cancer cell invasion in vitro by decreasing MMP-1, -2 and –9 mRNA, MMP-9 protein, and MMP-2 and –9 activity exclusive of ATRA and RAR. In vitro, ATRA reduces breast cancer cell invasion by decreasing MMP-9 activity (105). ATRA has also been shown to decrease MMP-1 and -9 activity in diabetic human skin organ culture (106) and MMP-7 protein excretion and active MMP-7 levels in the human colon cancer cell line, BM314 (88). ATRA has been 57

shown to decrease MMP-1 mRNA levels in MDA-MB-231 cells (107) and decrease MMP-1 and –2 mRNA and protein levels while increasing TIMP-1 and 2 protein levels in cultured melanoma cells (108). Treatment of rat invasive prostate adenocarcinoma cells with ATRA decreased cell invasion by inhibiting MMP-2 and -9 activity (109). Finally, ATRA has also been shown to decrease MMP-9 and increase TIMP-1 gene expression in murine lung alveolar carcinoma (110). These studies indicate that ATRA can alter MMP mRNA, protein and enzyme activity levels as well as increase TIMP-1 concentrations in a variety of cell systems. In the studies mentioned above, the MMP affected by ATRA varied with cell type, reflecting our data. Interestingly, MMP-2 and- 9 appear to be the most frequently regulated by ATRA. Serum and tissue levels of the gelatinases MMP-2 and –9 are correlated with colon cancer stage and prognosis in animal and clinical studies [For a review please see: (9)]. Collins et al (10) and Ornstein and Cohn (11) showed that MMP-2 mRNA was significantly increased in Duke’s stage B and C tumors. Koumura et al (111) found that a higher incidence of MMP-9 expression in colorectal tumors occurred when liver metastases were present. MMP-2 protein levels also increase as polyps progress to adenocarcinoma (112) and are increased in Duke’s D stage (13,14). In addition, MMP- 2 protein is found at the invasive edge of colon tumors (113). MMP-2 activation has also been shown to be increased in patients with metastases (15). Elevated active MMP-2 was found in the bile of patients with liver metastases when compared to patients with colon cancer but without liver metastases (114). Like MMP-2, increased MMP-9 protein and activity levels are also associated with Duke’s staging (13). MMP-9 is more frequently expressed in the invasive regions of advanced tumors (115). Serum MMP-9 58

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