Upregulation of retinoic acid receptor-beta by the epidermal growth factor-receptor inhibitor PD153035 is not mediated by blockade of ErbB pathways.
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-beta2 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-beta mRNA half-life. No other retinoid receptor, nor estrogen receptor-alpha, nor RASSF1A 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.
Grunt
Thomas W
TW
Department of Medicine I, Division of Oncology, Signaling Networks Program, Medical University of Vienna, Vienna, Austria. thomas.grunt@meduniwien.ac.at
Tomek
Katharina
K
Wagner
Renate
R
Puckmair
Klaudia
K
Kainz
Birgit
B
Rünzler
Dominik
D
Gaiger
Alexander
A
Köhler
Gottfried
G
Zielinski
Christoph C
CC
D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D018899:CpG Islands / Q000502:physiology; D019175:DNA Methylation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D005260:Female; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D010051:Ovarian Neoplasms; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology*; D012323:RNA Processing, Post-Transcriptional / Q000187:drug effects; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D020032:Tyrphostins / Q000494:pharmacology; D015854:Up-Regulation / Q000502:physiology
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011799:Quinazolines; D018168:Receptors, Retinoic Acid; D020032:Tyrphostins; C082925:retinoic acid receptor beta; C101044:RTKI cpd; D066246:ErbB Receptors; D000077156:Gefitinib; C088860:4-((3-bromophenyl)amino)-6,7-dimethoxyquinazoline