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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

levels, although

levels, although of inactive MMP, are also elevated in patients with liver metastases (114). As mentioned previously, TIMPs inhibit MMP activation. Although TIMP-1 is capable of affecting the activity of many MMP, TIMP-1 specifically binds to pro-MMP- 9, inhibiting its activation [For a review please see: (9)]. Our data show that retinol treatment increases TIMP-1 protein levels in the medium of both cell lines (Fig. 3.6). The increase in media TIMP-1 levels (Fig. 3.6A and B) occurs concomitant with decreased MMP–9 activity in both cell lines (Fig. 3.4). It is possible that TIMP-1 may bind to and prevent the activation of any pro-MMP-9 present in the culture media, thereby inhibiting cell invasion, however no pro-MMP-9 was detected in the tissue culture media (Fig. 3.4). Therefore, the lower MMP-9 activity most likely reflects the decrease in MMP-9 mRNA and protein levels, and not the increase in media TIMP-1 protein, that occurs in response to retinol treatment (Fig. 3.3 and 3.5). In contrast to what might be expected based on in vitro studies (116-118), elevated serum TIMP-1 levels are correlated with a poor disease outcome in clinical studies (119-122). In such cases, TIMP’s tumor promoting activities were not linked to its ability to inhibit MMP (123-126). Rather, the poor clinical outcome of patients with elevated TIMP-1 levels is thought to be due to the stimulatory activity of TIMP-1 on cell growth. However, in our study, retinol did not affect cell growth after 24 h of treatment (data not shown), the time at which media levels of TIMP-1 were measured. The link between serum TIMP-1 levels, MMP activity, and clinical outcome requires further study. Because our study used Matrigel-coated Boyden chambers, it lacked the full complement of ECM proteins that occur in vivo, therefore future studies will be 59

conducted utilizing an animal model to assess the effect of retinol on MMP and TIMP-1 levels on colon cancer metastasis. In conclusion, the present study shows that retinol inhibits colon cell invasion by decreasing MMP activity and increasing TIMP-1 levels in vitro through an ATRA and RAR-independent mechanism. While the particular MMP affected varied with cell line, MMP-9 mRNA and protein levels were decreased in both ATRA-resistant cell lines examined. Retinol also increased TIMP-1 levels in conditioned media obtained from both cell lines. The ability of retinol to decrease the metastatic potential of ATRA- resistant colon cancer cell lines suggests that dietary vitamin A supplementation may prevent colon cancer progression. ACKNOWLEDGEMENTS This research was supported by American Cancer Society Research Scholar Grant # 03-233-01-CNE and NIEHS Center Grant #ES 07784. The authors thank Dr. Rosh Chandraratna, formerly of Allergan Pharmaceuticals, Irvine, CA, for the gift of the RAR- pan antagonist, AGN 193109. They also thank Dr. Surangi Dharmawardhane and Nicolas Azios of the Universidad Central de Caribe for their technical assistance, Kally O’Reilly of the University of Texas at Austin for her editorial assistance, and Chris Morgan for his assistance with the migration assays. 60

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