Abstract
Retinoids have been shown to serve promising therapeutic agents for human cancers, e.g. the treatment of neuroblastoma. Synthetic retinoids, specific for particular retinoic acid (RA) receptors, are tested as new therapy strategies. In the present study, application of recombinant retinoic acid (RA) lowers retinoblastoma (RB) cell viability and induces apoptosis in RB cell lines. Combined treatment of RA and bone morphogenetic protein 4 (BMP-4) increases the pro-apoptotic effect of RA in the RB cells lines WERI-Rb1, Y-79, RB355, RBL-30 and RBL-15, indicating an additive effect. We could show that in WERI-Rb1 cells RA/BMP-4 mediated cell death is at least partially caspase-dependent, whereby RA and BMP-4 additively increased (i) Apaf-1 mRNA levels, (ii) caspase-9 cleavage activity and (iii) the number of activated, cleaved caspase-3 positive cells. Compared to single application of RA and BMP-4, combined RA/BMP-4 treatment significantly augments mRNA levels of the retinoic acid receptors (RARs) RARα and RARß and the retinoic X receptor (RXR) RXRγ suggesting an interaction in the induction of these RA receptor subtypes in WERI-Rb1 cells. Agonist studies revealed that both, RARs and RXRs are involved in RA/BMP-4 mediated apoptosis in WERI-Rb1 retinoblastoma cells. Employing specific RAR subtype antagonists and a RXRß and RXRγ knockdown, we proved that RA/BMP-4 apoptosis signaling in WERI-Rb1 cells requires the RA receptor subtypes RARα, RARß, RXRß and RXRγ. Deciphering signaling mechanisms underlying apoptosis induction of RA and BMP-4 in WERI-Rb1 cells, our study provides useful starting-points for future retinoid-based therapy strategies in retinoblastoma.
Highlights
IntroductionThe effects of retinoids are mediated by two classes of nuclear receptors, the retinoic acid receptors (RARs) and the retinoic X receptors (RXRs)
Retinoids, natural and synthetic vitamin A derivatives, are known to inhibit tumor growth and to suppress carcinogenesis, e.g. in MCF-7 breast cancer and Hep 3B cells [1; 2].The effects of retinoids are mediated by two classes of nuclear receptors, the retinoic acid receptors (RARs) and the retinoic X receptors (RXRs)
Employing specific RAR subtype antagonists and a RXRß and RXRγ knockdown, we proved that RA/Bone Morphogenetic Protein 4 (BMP-4) apoptosis signaling in WERIRb1 cells requires the RA receptor subtypes RARα, RARß, RXRß and RXRγ
Summary
The effects of retinoids are mediated by two classes of nuclear receptors, the retinoic acid receptors (RARs) and the retinoic X receptors (RXRs). All-trans-RA acid (ATRA) directly activates only RARs. in some cells ATRA is converted to 9-cis-RA and this retinoid directly activates RARs and RXRs [7; 8]. In some cells ATRA is converted to 9-cis-RA and this retinoid directly activates RARs and RXRs [7; 8] Due to their regulatory potential, RARs and RXRs are major drug targets for a variety of pathologies, including cancer. Former studies indicated that up-regulation of the RARß gene plays a critical role in mediating the apoptosis-inducing effect of retinoids in many different types of cancer cells [11,12,13]. Retinoids serve as promising therapeutic agents for many human cancers [9; 16,17,18,19]
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