Upregulation of retinoic acid receptor-β by the epidermal growth factor-receptor inhibitor PD153035 is not mediated by blockade of ErbB pathways
✍ Scribed by Thomas W. Grunt; Katharina Tomek; Renate Wagner; Klaudia Puckmair; Birgit Kainz; Dominik Rünzler; Alexander Gaiger; Gottfried Köhler; Christoph C. Zielinski
- Publisher
- John Wiley and Sons
- Year
- 2007
- Tongue
- English
- Weight
- 596 KB
- Volume
- 211
- Category
- Article
- ISSN
- 0021-9541
No coin nor oath required. For personal study only.
✦ Synopsis
Abstract
Inhibiting epidermal growth factor‐receptor (ErbB‐1) represents a powerful anticancer strategy. Activation of retinoid pathways is also in development for cancer treatment. Retinoic acid receptor‐β—the tumor suppressor and main retinoid mediator—‐is silenced in many tumors. The ErbB‐1 inhibitor PD153035 cooperates with retinoic acid during growth inhibition and induces retinoic acid receptor‐β suggesting that ErbB‐1 controls retinoic acid receptor‐β. However, here we demonstrate that ErbB pathways are not involved in PD153035‐mediated retinoic acid receptor‐β‐upregulation. PD153035 inhibits ErbB‐1‐phosphorylation, whereas its derivative EBE‐A22 is inactive. Yet both inhibit cell growth and upregulate retinoic acid receptor‐β in ErbB‐1‐overexpressing (MDA‐MB‐468), moderately expressing (OVCAR‐3), ErbB‐1‐negative (MDA‐MB‐453) or ErbB‐negative cells (CEM, Jurkat). Both bind DNA, whereas the closely related ErbB‐1 inhibitors AG1478 and ZD1839, which are inactive on retinoic acid receptor‐β, do not significantly bind DNA. None of the other ErbB‐1/ErbB‐2 inhibitors tested (RG‐14620, LFM‐A12, AG879, AG825) affect retinoic acid receptor‐β. PD153035 decreases methylation of the retinoic acid receptor‐β2 promoter. In OVCAR‐3, it stimulates dislodgement of histone deacetylase 1 from the promoter and acetylation of histones H3 and H4. Consequently, PD153035 facilitates recruitment of RNA polymerase II to the promoter and stimulates transcriptional activity. Moreover, PD153035 increases the retinoic acid receptor‐β mRNA half‐life. No other retinoid receptor, nor estrogen receptor‐α, nor RASSF1A is upregulated by PD153035. Thus PD153035 induces retinoic acid receptor‐β by ErbB‐independent transcriptional and post‐transcriptional mechanisms. This report highlights a triple action for an ErbB‐1 inhibitor (ErbB‐1 inhibition, DNA intercalation, retinoic acid receptor‐β‐induction). Such multitargeting drugs bear great potential for cancer treatment. J. Cell. Physiol. 211: 803–815, 2007. © 2007 Wiley‐Liss, Inc.