Retinoids cause apoptosis in pancreatic cancer cells via activation of RAR-gamma and altered expression of Bcl-2/Bax.
All-trans-retinoic acid and 9-cis-retinoic acid have been reported to have inhibitory effects on pancreatic adenocarcinoma cells and we have shown that this is partly due to induction of apoptosis. In this study, the mechanisms whereby 9-cis-retinoic acid induces apoptosis in these cells were investigated. An involvement of the Bcl-2 family of proteins was shown, such that 9-cis-retinoic acid causes a decrease in the Bcl-2/Bax ratio. Overexpression of Bcl-2 also resulted in inhibition of apoptosis induced by 9-cis-retinoic acid. Furthermore, two broad-range caspase inhibitors blocked DNA fragmentation induced by 9-cis-retinoic acid, but had no effect on viability defined by mitochondrial activity. Using synthetic retinoids, which bind selectively to specific retinoic acid receptor subtypes, we further established that activation of retinoic acid receptor-gamma is essential for induction of apoptosis. Only pan-retinoic acid receptor and retinoic acid receptor-gamma selective agonists reduced viability and a cell line expressing very low levels of retinoic acid receptor-gamma is resistant to the effects of 9-cis-retinoic acid. A retinoic acid receptor-beta/gamma selective antagonist also suppressed the cytotoxic effects of 9-cis-retinoic acid in a dose-dependent manner. This study provides important insight into the mechanisms involved in suppression of pancreatic tumour cell growth by retinoids. Our results encourage further work evaluating the clinical use of receptor subtype selective retinoids in pancreatic carcinoma.
Pettersson
F
F
Department of Oncology, Gastroenterology, Endocrinology and Metabolism, St George's Hospital Medical School, London SW17 ORE, UK.
Dalgleish
A G
AG
Bissonnette
R P
RP
Colston
K W
KW
D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology*; D000077556:Alitretinoin; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D053938:DNA Fragmentation / Q000187:drug effects; D004351:Drug Resistance; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D019254:Genes, bcl-2; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000187:drug effects; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000473:pathology*; D020033:Protein Isoforms / Q000187:drug effects / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis*; D018168:Receptors, Retinoic Acid / Q000187:drug effects* / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000502:physiology; D047488:Retinoid X Receptors; D012176:Retinoids / Q000819:agonists / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D014157:Transcription Factors / Q000187:drug effects / Q000502:physiology; D014162:Transfection; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D051028:bcl-2-Associated X Protein; D000097768:Retinoic Acid Receptor gamma
D000077556:Alitretinoin; D000590:Amino Acid Chloromethyl Ketones; D001224:Aspartic Acid; D015853:Cysteine Proteinase Inhibitors; D005231:Fatty Acids, Unsaturated; D009363:Neoplasm Proteins; D020033:Protein Isoforms; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D018168:Receptors, Retinoic Acid; D011993:Recombinant Fusion Proteins; D047488:Retinoid X Receptors; D012176:Retinoids; D014157:Transcription Factors; D014212:Tretinoin; D051028:bcl-2-Associated X Protein; D000097768:Retinoic Acid Receptor gamma; C494826:BAX protein, human; C494827:Bax protein, mouse; C413643:benzyloxycarbonyl-aspartyl(O-methyl)fluoromethane; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C062198:octa-2,4,6-trienoic acid