Retinoic acid receptor alpha mediates growth inhibition by retinoids in rat pancreatic carcinoma DSL-6A/C1 cells.
During carcinogenesis, pancreatic acinar cells can dedifferentiate into 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 antiproliferative actions of retinoids. Treatment of DSL-6A/C1 cells with retinoids results in a time- and dose-dependent inhibition of cell growth, paralleled by a retinoid-mediated transactivation of a pTK::betaRAREx2-luciferase reporter construct transiently transfected into DSL-6A/C1 cells. Retinoid receptor expression was evaluated by reverse transcriptase 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 inhibition. Furthermore, all-trans-retinoic acid-mediated growth inhibition and transactivation was completely blocked by the RAR-alpha-specific antagonist Ro 41-5253. In summary, the RAR-alpha subtype predominantly mediates the antiproliferative effects of retinoids in DSL-6A/C1 cells. Furthermore, this cell system provides a feasible tool to study the molecular mechanisms underlying the growth inhibitory effects of retinoids in ductal pancreatic carcinoma cells derived from a primary acinar cell phenotype.
Brembeck
F H
FH
Department of Gastroenterology, Medizinische Klinik I, Klinikum Benjamin Franklin, FU Berlin/Germany.
Kaiser
A
A
Detjen
K
K
Hotz
H
H
Foitzik
T
T
Buhr
H J
HJ
Riecken
E O
EO
Rosewicz
S
S
D000818:Animals; D018270:Carcinoma, Ductal, Breast / Q000378:metabolism / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D002471:Cell Transformation, Neoplastic; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology; D051381:Rats; D018168:Receptors, Retinoic Acid / Q000096:biosynthesis / Q000502:physiology*; D012176:Retinoids / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D018168:Receptors, Retinoic Acid; D012176:Retinoids