Retinol decreases beta‐catenin protein levels in retinoic acid (RA)‐resistant colon cancer cell lines via a RXR‐mediated degradation pathway

Abstract

Excess nuclear beta-catenin induces colon cancer cell division. The objective of this study was to examine the effect of retinol on beta-catenin protein degradation. Three RA-resistant colon cancer cell lines were treated with 0, 0.1, 1 and 10 microM retinol for 1–4 d. Retinol reduced beta-catenin protein levels in a dose-responsive manner in all cell lines. Treatment with the proteasomal inhibitor, MG132, blocked the retinol-induced decrease in beta-catenin indicating retinol decreases beta-catenin via proteasomal degradation. Multiple pathways direct beta-catenin to the proteasome for degradation including a p53/Siah-1/adenomatous polyposis coli [APC], a Wnt/glycogen synthase kinase-3beta/APC, and a retinoid “X” receptor [RXR]-mediated pathway. Due to mutations in beta-catenin (HCT-116), APC (SW620), and p53 (WiDr) only the RXR-mediated pathway remains functional in all three cell lines. To test if RXRs mediate beta-catenin degradation, cells were treated with the RXR antagonist, PA452. PA452 blocked the retinol-induced decrease in beta-catenin protein. In contrast to retinol treatment, the RXR agonists, 9 cis-retinoic acid and PA024 only slightly reduced beta-catenin protein levels revealing that the RXR-mediated degradation pathway may not require a ligand-bound RXR. Decreased beta-catenin levels reflect growth inhibition in all three RA-resistant colon cancer cell lines indicating that retinol may regulate cell growth via a mechanism involving intracellular beta-catenin signaling. Funding: ACS Grant # 03-233-01-CNE.