title: Retinol inhibits the growth of all-trans-retinoic acid-sensitive and all-trans-retinoic acid-resistant colon cancer cells through a retinoic acid receptor-independent mechanism.
abstract: 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, retinoic acid 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 converted 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-chloramphenicol acetyltransferase (CAT) and treated with ATRA and retinol. Although treatment with ATRA increased CAT activity 5-fold in ATRA-sensitive cells, retinol treatment did not increase CAT activity in any cell line examined. To show that growth inhibition due to retinol was ATRA, RAR, and RARE independent, a pan-RAR antagonist was used to block RAR signaling. Retinol-induced growth inhibition was not alleviated by the RAR antagonist in any cell line, but the antagonist alleviated ATRA-induced growth inhibition of HCT-15 cells. Retinol did not induce apoptosis, differentiation or necrosis, but affected cell cycle progression. Our data show that retinol acts through a novel, RAR-independent mechanism to inhibit colon cancer cell growth.
authors.affiliation: Institute for Cell and Molecular Biology and Division of Nutritional Sciences, Department of Human Ecology, University of Texas at Austin, Austin, Texas 78712, USA.
authors.forename: Eun Young
authors.initials: EY
authors.lastname: Park
authors.forename: Alice
authors.initials: A
authors.lastname: Dillard
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Williams
authors.forename: Erik T
authors.initials: ET
authors.lastname: Wilder
authors.forename: M Reese
authors.initials: MR
authors.lastname: Pepper
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Lane
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D015500:Chloramphenicol O-Acetyltransferase / Q000096:biosynthesis / Q000235:genetics; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D045325:HCT116 Cells; D006801:Humans; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D020218:Response Elements; D014162:Transfection; D014212:Tretinoin / Q000494:pharmacology*; D014801:Vitamin A / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D018168:Receptors, Retinoic Acid; D014801:Vitamin A; D014212:Tretinoin; D015500:Chloramphenicol O-Acetyltransferase