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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

The

The retinoids, a group of compounds consisting of vitamin A (retinol), its natural metabolites, and several synthetic compounds, have been shown to inhibit metastasis in a variety of model systems. For example, dietary retinyl palmitate supplementation decreases malignant melanoma metastasis in mice (86). In addition, all-trans-retinoic acid (ATRA), an active metabolite of dietary vitamin A, decreases gastric cancer (87) and colon cancer cell invasion (88) in vivo. Numerous studies have shown that ATRA reduces tumor cell invasion and metastasis in vitro by decreasing MMP mRNA, protein levels or enzyme activity as well as increasing TIMP mRNA or protein levels. However, to our knowledge, the ability of retinol, the form of vitamin A derived from the diet, to inhibit tumor cell invasion by altering MMP mRNA and protein levels or activity has not been explored. ATRA exerts its effects by binding to retinoic acid receptors (RARs). The RARs function as heterodimers with retinoic X receptors (RXRs). When ligand bound, the RAR/RXR heterodimer activates gene transcription via retinoic acid response elements (RAREs) located in the regulatory regions of retinoid-responsive genes [for a review please see (89)]. The clinical effectiveness of ATRA is limited by ATRA- resistance, defined as the inability of ATRA to inhibit cell growth and induce differentiation. ATRA-resistance is a common phenomenon associated with cancer progression and is believed to be due to the inability of ATRA to induce RAR gene expression in ATRA-resistant cells (90-93). Because the diet contains almost no ATRA, the use of exogenous ATRA to study the effects of vitamin A assumes that all of the biological phenomena attributed to retinol are due to ATRA. Preformed dietary vitamin A is consumed as retinyl esters that are 43

cleaved within the intestinal lumen to yield retinol. The concentration of ATRA in the circulation is very low (1-14 nM) (94). In contrast, serum retinol concentrations range from 0.5 to 2 μM (55). Therefore, colonocytes are primarily exposed to retinol, the focus of the present study, via the diet and the circulation. We have previously shown that retinol, but not ATRA, inhibits the growth of ATRA-resistant colon cancer cell lines through an ATRA and RAR-independent mechanism (95). The use of ATRA-resistant cell lines allows us to examine the effects of retinol exclusive of those of ATRA. For example, the ATRA resistant cell lines used in this study lack one or more of the RAR and either lack the ability to metabolize retinol to ATRA, as is the case for the SW620 cell line, or produce only very small amounts of ATRA from retinol, as is the case for the HCT-116 cell line (95). Importantly, treatment of these cells lines with ATRA or retinol does not induce the transcription of a RARE-chloramphenicol acetyltransferase (CAT) reporter construct in either cell line and the RAR pan-antagonist, AGN 193109, was unable to block the inhibitory effects of retinol on tumor cell growth (95). Inhibition of primary tumor growth is only one aspect of a successful chemotherapeutic agent, therefore the objective of the present study was to examine the ability of retinol to inhibit ATRA-resistant colon cancer cell metastasis in vitro. Because ATRA has been shown to inhibit cell invasion by decreasing MMP activity and increasing TIMP, we also explore the effect of retinol on MMP mRNA and protein levels, MMP enzyme activity, and TIMP protein concentration. 44

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