title: Anticancer effect of retinoic acid via AP-1 activity repression is mediated by retinoic acid receptor alpha and beta in gastric cancer cells.
abstract: To uncover the mechanisms relating to the anticancer effect of retinoic acids in gastric cancer cells, the mediation of activator protein-1 (AP-1) activity repression by retinoic acid receptors (RARs) was investigated. All-trans retinoic acid (ATRA) inhibited AP-1 activity in BGC-823 cells (RARalpha(+), RARbeta(+)), but not in MKN-45 cells (RARalpha(lo), RARbeta(-)). Transient transfection of RARbeta expression vector into MKN-45 cells significantly resulted in direct repression of AP-1 activity in a receptor concentration-dependent manner, and this could be strengthened by ATRA. Stable transfection of RARbeta into MKN-45 cells directly inhibited cell growth and colony formation, and ATRA also enhanced these effects. Transient transfection of RARalpha into MKN-45 cells however, displayed receptor concentration-dependent AP-1 activity inhibition only in the presence of ATRA. Stable transfection of RARalpha into MKN-45 cells resulted in ATRA-dependent inhibition of cell growth and colony formation. For AP-1 binding activity induced by TPA, the repressive effect of ATRA was only observed in BGC-823 and RARalpha and RARbeta stably transfected MKN-45 cells, but not in intact MKN-45 cells. This indicates the necessity for sufficient cellular RARalpha and/or RARbeta in order for AP-1 activity repression to occur. Deletion of DNA binding domain (DBD) of RARbeta, but not ligand binding domain (LBD), eliminated the anti-AP-1 function of RARbeta. It is therefore concluded that both RARalpha and RARbeta are mediators in the anticancer function of ATRA via AP-1 activity inhibition, and that RARbeta, not RARalpha, can inhibit AP-1 activity to a certain extent directly by itself. Thus DBD, not LBD, is critical for anti-AP-1 activity.
authors: Key Laboratory of the Ministry of Education for Cell Biology and Tumor Cell Engineering, School of Life Sciences, Xiamen University, Fujian Province, China. xgwu@nmu.edu.cn
authors: Qiao
authors: Q
authors: Wu
authors: Zheng-ming
authors: ZM
authors: Chen
authors: Wen-jin
authors: WJ
authors: Su
mesh_terms: D000970:Antineoplastic Agents / Q000378:metabolism* / Q000494:pharmacology; D002455:Cell Division / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D017930:Genes, Reporter; D006801:Humans; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism*; D000072482:Retinoic Acid Receptor alpha; D013274:Stomach Neoplasms / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014212:Tretinoin / Q000378:metabolism / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D018808:Transcription Factor AP-1; C082925:retinoic acid receptor beta; D014212:Tretinoin; D013755:Tetradecanoylphorbol Acetate