The mechanism by which retinol decreases β-catenin protein in retinoic acid-resistant colon cancer cells

Abstract

Cancer is the second leading cause of death in the United States, following cardiovascular disease. Colorectal cancer is the third leading cause of cancer death in the United States in both men and women (1). The American Cancer Society predicts over 153,000 new colorectal cancer cases and over 52,000 deaths due to colorectal cancer in 2007 (1). Even though the mortality rate has continued to decrease for colorectal cancer in both men and women, there is only a 64% five-year survival rate, unless a distant metastasis is diagnosed, in which case the five-year survival rate drops to only 10%. All-trans retinoic acid (ATRA) is currently used as a chemotherapy for acute promyelocytic leukemia and some forms of skin cancer. Unfortunately, chemotherapy with ATRA often results in unpleasant side effects and ATRA-resistant tumors are common due to defects in ATRA signaling. The focus of this study is retinol’s effects on β- catenin, a protein essential for colon carcinogenesis. Our goal is to understand the mechanism by which retinol decreases the growth of ATRA-resistant human colon cancer cells. We first determined that retinol, not ATRA, decreases the growth of ATRA-resistant colon cancer cell lines by slowing cell cycle progression. Next, we examined the effects of retinol treatment on β- catenin, a protein which regulates the transcription of cyclin D1 and c-myc, a protein essential for progress through the cell cycle. We found that retinol significantly decreased β-catenin protein by inducing retinoid X receptor (RXR)α-mediated proteasomal degradation. Lastly, we showed that RXRα directs the degradation of β-catenin by binding β-catenin and transporting it to the proteasome for degradation. Based on these results, we propose a mechanism where retinol increases RXRα protein levels and RXRα-β-catenin binding as well as the movement of β-catenin to the cytosol where it is proteosomally degraded, ultimately leading to slowed cell cycle progression.