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Retinol decreases beta‐catenin protein levels in retinoic acid (RA)‐resistant colon cancer cell lines via a RXR‐mediated degradation pathway
Author(s) -
Dillard Alice C,
Lane Michelle A
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a560-a
Subject(s) - retinoic acid , retinol , beta catenin , wnt signaling pathway , retinoid x receptor , mg132 , cancer research , chemistry , biology , cell culture , microbiology and biotechnology , endocrinology , signal transduction , biochemistry , proteasome inhibitor , proteasome , vitamin , nuclear receptor , transcription factor , genetics , gene
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.