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Upregulation of retinoic acid receptor‐β by the epidermal growth factor‐receptor inhibitor PD153035 is not mediated by blockade of ErbB pathways
Author(s) -
Grunt Thomas W.,
Tomek Katharina,
Wagner Renate,
Puckmair Klaudia,
Kainz Birgit,
Rünzler Dominik,
Gaiger Alexander,
Köhler Gottfried,
Zielinski Christoph C.
Publication year - 2007
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.20990
Subject(s) - retinoid x receptor gamma , retinoic acid receptor , retinoic acid receptor beta , retinoic acid receptor alpha , cancer research , retinoic acid , epidermal growth factor receptor , downregulation and upregulation , biology , erbb , retinoid x receptor alpha , retinoic acid inducible orphan g protein coupled receptor , retinoic acid receptor gamma , chemistry , microbiology and biotechnology , signal transduction , receptor , biochemistry , gene
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.