Upregulation of retinoic acid receptor-β by the epidermal growth factor-receptor inhibitor PD153035 is not mediated by blockade of ErbB pathways

被引：11
作者：
Grunt, Thomas W.
Tomek, Katharina
Wagner, Renate
Puckmair, Klaudia
Kainz, Birgit
Ruenzler, Dominik
Gaiger, Alexander
Koehler, Gottfried
Zielinski, Christoph C.
机构：
[1] Med Univ Vienna, Dept Med 1, Signaling Networks Program, Div Oncol, A-1090 Vienna, Austria
[2] Med Univ Vienna, Dept Med 1, Div Hematol & Hemostaseol, A-1090 Vienna, Austria
[3] Univ Vienna, Dept Biomol Struct Chem, Max F Perutz Labs, A-1010 Vienna, Austria
来源：
JOURNAL OF CELLULAR PHYSIOLOGY | 2007年 / 211卷 / 03期
关键词：
D O I：
10.1002/jcp.20990
中图分类号：
Q2 [细胞生物学];
学科分类号：
071009 ; 090102 ;
摘要：
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-beta-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-beta suggesting that ErbB-1 controls retinoic acid receptor-beta. However, here we demonstrate that ErbB pathways are not involved in PD153035-mediated retinoic acid receptor-beta-upregulation. PD153035 inhibits ErbB-1-phosphorylation, whereas its derivative EBE-A22 is inactive. Yet both inhibit cell growth and upregulate retinoic acid receptor-beta 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-beta, 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-beta. PD153035 decreases methylation of the retinoic acid receptor-beta 2 promoter. In OVCAR-3, it stimulates dislodgement of histone deacetylase I 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-beta mRNA half-life. No other retinoid receptor, nor estrogen receptor-alpha, nor RASSFIA is upregulated by PD153035. Thus PD153035 induces retinoic acid receptor-beta 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-beta-induction). Such multitargeting drugs bear great potential for cancer treatment.
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收藏
页码：803 / 815
页数：13
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