Limits...
Retinoids cause apoptosis in pancreatic cancer cells via activation of RAR-gamma and altered expression of Bcl-2/Bax.

Pettersson F, Dalgleish AG, Bissonnette RP, Colston KW - Br. J. Cancer (2002)

Bottom Line: 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.Our results encourage further work evaluating the clinical use of receptor subtype selective retinoids in pancreatic carcinoma.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, Gastroenterology, Endocrinology and Metabolism, St George's Hospital Medical School, London SW17 ORE, UK.

ABSTRACT
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.

Show MeSH

Related in: MedlinePlus

Semi-quantitative Western blots showing expression of RAR-α, -β and -γ and RXR-α in AsPc-1, BxPc-3, T3M-4 and A818-4 pancreatic adenocarcinoma cell lines. Equal amounts of total protein was loaded on the gel, based on the Bradford assay.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2376147&req=5

fig5: Semi-quantitative Western blots showing expression of RAR-α, -β and -γ and RXR-α in AsPc-1, BxPc-3, T3M-4 and A818-4 pancreatic adenocarcinoma cell lines. Equal amounts of total protein was loaded on the gel, based on the Bradford assay.

Mentions: Expression of RAR-α, β and γ and RXR-α was assessed in AsPc-1, BxPc-3, T3M-4 and A818-4 cells, using semi-quantitative Western blotting. Weak expression of RAR-α was detected in the four cell lines, whereas very weak expression of RAR-β could be detected in T3M-4 only. RAR-γ was expressed in AsPc-1, BxPc-3 and T3M-4 cells, but only very weakly in 9cRA-resistant A818-4 cells. Approximately equal levels of RXR-alpha were seen in all four cell lines (Figure 5Figure 5


Retinoids cause apoptosis in pancreatic cancer cells via activation of RAR-gamma and altered expression of Bcl-2/Bax.

Pettersson F, Dalgleish AG, Bissonnette RP, Colston KW - Br. J. Cancer (2002)

Semi-quantitative Western blots showing expression of RAR-α, -β and -γ and RXR-α in AsPc-1, BxPc-3, T3M-4 and A818-4 pancreatic adenocarcinoma cell lines. Equal amounts of total protein was loaded on the gel, based on the Bradford assay.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2376147&req=5

fig5: Semi-quantitative Western blots showing expression of RAR-α, -β and -γ and RXR-α in AsPc-1, BxPc-3, T3M-4 and A818-4 pancreatic adenocarcinoma cell lines. Equal amounts of total protein was loaded on the gel, based on the Bradford assay.
Mentions: Expression of RAR-α, β and γ and RXR-α was assessed in AsPc-1, BxPc-3, T3M-4 and A818-4 cells, using semi-quantitative Western blotting. Weak expression of RAR-α was detected in the four cell lines, whereas very weak expression of RAR-β could be detected in T3M-4 only. RAR-γ was expressed in AsPc-1, BxPc-3 and T3M-4 cells, but only very weakly in 9cRA-resistant A818-4 cells. Approximately equal levels of RXR-alpha were seen in all four cell lines (Figure 5Figure 5

Bottom Line: 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.Our results encourage further work evaluating the clinical use of receptor subtype selective retinoids in pancreatic carcinoma.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, Gastroenterology, Endocrinology and Metabolism, St George's Hospital Medical School, London SW17 ORE, UK.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus