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

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-cisretinoic 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-g is essential for induction of apoptosis. Only pan-retinoic acid receptor and retinoic acid receptor-g selective agonists reduced viability and a cell line expressing very low levels of retinoic acid receptor-g is resistant to the effects of 9-cis-retinoic acid. A retinoic acid receptor-b/ g 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.

A novel retinoid-related molecule inhibits pancreatic cancer cell proliferation by a retinoid receptor independent mechanism via suppression of cell cycle regulatory protein function and induction of caspase-associated apoptosis

“…Many pancreatic cancer cell lines express RARa and RXRg, although other RAR and RXR subtypes are also expressed (Albrechtsson et al, 2002) and previous studies show that natural retinoids can inhibit pancreatic cancer cell proliferation (Egawa et al, 1996;Rosewicz et al, 1996;Kawa et al, 1997;Brembeck et al, 1998a;Pettersson et al, 2001Pettersson et al, , 2002Albrechtsson et al, 2002). Some reports suggest that the retinoidassociated inhibition of pancreatic cancer cell proliferation is RARa receptor dependent (Kaiser et al, 1998;Brembeck et al, 1998a;Pettersson et al, 2002). For example, treating DSL-6A/C1 pancreatic adenocarcinoma cells with an RARa-selective synthetic retinoid suppresses cell proliferation, while treatment with an RARa-antagonist reverses this response (Brembeck et al, 1998a).…”

“…The RAR and RXR receptor subgroups each include a, b and g isoforms. RARa, b and g bind to all-trans retinoic acid, while RXRa, b and g interact with 9-cis-retinoic acid (Zelent et al, 1989;Heyman et al, 1992;Mangelsdorf et al, 1992;Rosewicz et al, 1995;Kawa et al, 1997;Pettersson et al, 2001Pettersson et al, , 2002.…”

Gambogic Acid Induces Apoptosis and Regulates Expressions of Bax and Bcl-2 Protein in Human Gastric Carcinoma MGC-803 Cells

“…16) Thus, the ratio of Bcl-2/Bax might be one a critical factor of a cell's threshold for undergoing apoptosis. 17) We deduce that Bax leads to the release of cytochrome c which is restrained by binding to Bcl-2. The activation of cytochrome c is suppressed, and subsequently apoptosis occurs.…”

Early mitochondrial alterations in ATRA-induced cell death

“…In this case, activation of proapoptotic Bcl-2 family proteins, such as Bid and Bax, results in permeabilization of the outer mitochondrial membrane and cytochrome c release. 10 ATRA was shown to downregulate the expression of the antiapoptotic protein Bcl-2, [11][12][13] which is known to inhibit cell death by interaction with proapoptotic Bcl-2 family members. However, in ATRAtreated cells, the initial triggering mechanism leading to the activation of Bid and Bax remains to be clarified.…”