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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 3: Retinol

Chapter 3: Retinol inhibits the invasion of retinoic acid-resistant colon cancer cells in vitro and decreases matrix metalloproteinase mRNA, protein, and activity levels ABSTRACT Retinol inhibits the growth of all-trans-retinoic acid (ATRA)-resistant human colon cancer cell lines through a retinoic acid receptor (RAR)-independent mechanism. The objectives of the current study were to determine if retinol inhibited the invasion of all-trans-retinoic acid (ATRA) -resistant colon cancer cells independent of RAR and the effects of retinol on matrixmetalloproteinases (MMP). Retinol inhibited the migration and invasion of two ATRA-resistant colon cancer cell lines, HCT-116 and SW620, in a dose-dependent manner. To determine if transcription, particularly RAR-mediated transcription, or translation of new genes was required for retinol to inhibit cell invasion, cells were treated with retinol and cycloheximide, actinomycin D, or a RAR pan- antagonist. Treatment of cells with retinol and cycloheximide, actinomycin D, or a RAR pan-antagonist did not block the ability of retinol to inhibit cell invasion. In addition, retinol decreased MMP-1 mRNA levels in both cell lines, MMP-2 mRNA levels in the SW620 and MMP-7 and -9 mRNA levels in the HCT-116 cell line. Retinol also decreased the activity of MMP-2 and -9 and MMP-9 protein levels while increasing TIMP (tissue inhibitor of matrixmetalloproteinase)-1 media levels. In conclusion, retinol reduces the metastatic potential of ATRA-resistant colon cancer cells via a novel 41

RAR-independent mechanism that may involve decreased MMP mRNA levels and activity. INTRODUCTION Colorectal cancer is the third most common cancer and cause of death due to cancer in the United States (1). Death is generally not due to the primary, localized tumor, but to the metastasis of the cancer to other tissues, primarily the liver. The escape of primary tumor cells into the circulation (intravasation) and the invasion of these tumor cells into the new target tissue (extravasation) to establish metastases requires digestion of and migration through the extracellular matrix (ECM). The digestion of the ECM is performed by matrixmetalloproteinases (MMP), a large family of proteases [For a review please see: (8,9)]. MMP are classified by their substrates into different groups, collagenases, gelatinases, stromelysins, membrane-type MMP, matrilysins, and macrophage elastases, etc. Increased serum or tissue levels and activity of MMP-1, -2, - 7, -9 and -13 are associated with colorectal cancer progression [(83,84); for a review please see: (9)]. MMP must be cleaved to be active and MMP activity is regulated both at cleavage and total protein levels. MMP activity is also regulated by TIMPs (tissue inhibitor of matrixmetalloproteinase), which function as endogenous protease inhibitors [For a review please see: (9,85)]. TIMP-1 inhibits the activity of all MMP. In addition, TIMP-1 binds to pro-MMP-9 to inhibit its conversion to active MMP-9. [For a review please see (9)]. 42

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