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

by Dillard, Alice Clare

Retinol (vitamin A) is thought to exert its effects through the actions of its metabolite, all-trans-retinoic acid (ATRA), on gene transcription mediated by retinoic acid receptors (RAR) and retinoic acid response elements (RARE). However, RA-resistance limits the chemotherapeutic potential of ATRA. We examined the ability of retinol to inhibit the growth of ATRA-sensitive (HCT-15) and ATRA-resistant (HCT-116, SW620, and WiDr) human colon cancer cell lines. Retinol inhibited cell growth in a dose-responsive manner. Retinol was not metabolized to ATRA or any bioactive retinoid in two of the cell lines examined. HCT-116 and WiDr cells did convert a small amount of retinol to ATRA, however this amount of ATRA was unable to inhibit cell growth. To show that retinol was not inducing RARE-mediated transcription, each cell line was transfected with pRARE-CAT (chloramphenicol acetyltransferase) and treated with ATRA and retinol. Although treatment with ATRA did increase CAT activity five-fold in ATRA-sensitive cells, retinol treatment did not increase CAT activity in any cell line examined. To demonstrate that growth inhibition due to retinol treatment was independent of ATRA, RAR, and RARE, a pan RAR-antagonist was used to block RARsignaling. Retinol-induced growth inhibition was not alleviated by the RAR-antagonist in any cell line, but the antagonist did alleviate ATRA-induced growth inhibition of HCT-15 cells. Retinol did not induce apoptosis, differentiation or necrosis, but did affect cell cycle progression. Our data show that retinol acts through a novel, RAR-independent mechanism to inhibit colon cancer cell growth. 28