RETINOIC ACID RECEPTOR-ALPHA MEDIATES GROWTH-INHIBITION BY RETINOIDS IN RAT PANCREATIC-CARCINOMA DSL-6A C1 CELLS/

During carcinogenesis, pancreatic acinar cells can dedifferentiate int o ductal adenocarcinoma of the pancreas. DSL-6A/C1 cells represent an in vitro model of this carcinogenic sequence. This study was designed to examine the effects of retinoids on cell growth in DSL-6A/C1 cells and to characterize further the molecular mechanisms underlying the an tiproliferative actions of retinoids, Treatment of DSL-6A/C1 cells wit h retinoids results in a time- and dose-dependent inhibition of cell g rowth, paralleled by a retinoid-mediated transactivation or a pTK::bet a RAREx2-luciferase reporter construct transiently transfected into DS L-6A/C1 cells. Retinoid receptor expression was evaluated by reverse t ranscriptase polymerase chain reaction (RT-PCR) using subtype-specific primers and demonstrated expression of retinoic acid receptor alpha ( RAR-alpha), RAR-beta and retinoid X receptor alpha (RXR-alpha). Using a panel of receptor subtype-specific agonists, the RAR-alpha specific agonist Ro 40-6055 was the most potent retinoid in terms of growth inh ibition. Furthermore, all-trans-retinoic acid-mediated growth inhibiti on and transactivation was completely blocked by the RAR-alpha-specifi c antagonist Ro 41-5253, In summary, the RAR-alpha subtype predominant ly mediates the antiproliferative effects of retinoids in DSL-6A/C1 ce lls. Furthermore, this cell system provides a feasible tool to study t he molecular mechanisms underlying the growth inhibitory effects of re tinoids in ductal pancreatic carcinoma cells derived from a primary ac inar cell phenotype.