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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

ATRA.

ATRA. The purpose of this study is to understand the mechanism by which retinol decreased the growth and progression of ATRA-resistant human colon cancer in vivo and in vitro. We first demonstrated that retinol decreased the growth of ATRA-resistant colon cancer cells by arresting cell cycle progression independent of the ATRA/RAR/RARE pathway. Next, we showed retinol inhibited ATRA-resistant human colon cancer cell invasion by decreasing MMP-2, -9 and PI3K activity in vitro. Finally, dietary vitamin A supplementation decreased the incidence and multiplicity of liver metastases in nude mice intrasplenically injected with ATRA-resistant human colon cancer cells. Taken together, these data suggest the possibility of dietary vitamin A supplementation for colon cancer therapy and prevention. vi

Table of Contents LIST OF TABLES IX LIST OF FIGURES X CHAPTER 1: INTRODUCTION 1 1. Colorectal Cancer................................................................................................ 1 1.1. Colorectal Cancer General Overview ..................................................... 1 1.2. Colon Cancer Metastasis......................................................................... 2 1.3. Dietary Chemoprevention of Colorectal Cancer..................................... 5 2. Retinol................................................................................................................. 6 3. Colon cancer and retinol ..................................................................................... 8 CHAPTER 2: RETINOL INHIBITS THE GROWTH OF ALL-TRANS-RETINOIC ACID- SENSITIVE AND -RESISTANT COLON CANCER CELLS THROUGH A RETINOIC ACID RECEPTOR-INDEPENDENT MECHANISM 12 ABSTRACT................................................................................................. 12 INTRODUCTION ....................................................................................... 13 MATERIALS AND METHODS................................................................. 15 RESULTS .................................................................................................... 20 DISCUSSION.............................................................................................. 26 ACKNOWLEDGEMENTS......................................................................... 30 CHAPTER 3: RETINOL INHIBITS THE INVASION OF RETINOIC ACID-RESISTANT COLON CANCER CELLS IN VITRO AND DECREASES MATRIX METALLOPROTEINASE MRNA, PROTEIN, AND ACTIVITY LEVELS 41 ABSTRACT................................................................................................. 41 INTRODUCTION ....................................................................................... 42 MATERIALS AND METHODS................................................................. 45 RESULTS .................................................................................................... 50 DISCUSSION.............................................................................................. 56 ACKNOWLEDGEMENTS......................................................................... 60 vii

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