Grunt Thomas W, Tomek Katharina, Wagner Renate, Puckmair Klaudia, Kainz Birgit, Rünzler Dominik, Gaiger Alexander, Köhler Gottfried, Zielinski Christoph C
Department of Medicine I, Division of Oncology, Signaling Networks Program, Medical University of Vienna, Vienna, Austria.
J Cell Physiol. 2007 Jun;211(3):803-15. doi: 10.1002/jcp.20990.
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.
抑制表皮生长因子受体（ErbB-1）是一种强有力的抗癌策略。维甲酸途径的激活也正在用于癌症治疗的研究中。维甲酸受体β——肿瘤抑制因子和主要的维甲酸介质——在许多肿瘤中都处于沉默状态。ErbB-1抑制剂PD153035在生长抑制过程中与维甲酸协同作用，并诱导维甲酸受体β，这表明ErbB-1控制维甲酸受体β。然而，我们在此证明，ErbB途径并不参与PD153035介导的维甲酸受体β上调。PD153035抑制ErbB-1磷酸化，而其衍生物EBE-A22无活性。然而，两者都能抑制细胞生长并上调维甲酸受体β，无论是在ErbB-1过表达（MDA-MB-468）、中度表达（OVCAR-3）、ErbB-1阴性（MDA-MB-453）还是ErbB阴性细胞（CEM、Jurkat）中。两者都能结合DNA，而与之密切相关的ErbB-1抑制剂AG1478和ZD1839对维甲酸受体β无活性，它们与DNA的结合不显著。所测试的其他ErbB-1/ErbB-2抑制剂（RG-14620、LFM-A12、AG879、AG825）均不影响维甲酸受体β。PD153035可降低维甲酸受体β2启动子的甲基化水平。在OVCAR-3细胞中，它能刺激组蛋白去乙酰化酶1从启动子上解离，并使组蛋白H3和H4乙酰化。因此，PD153035促进RNA聚合酶II募集到启动子上并刺激转录活性。此外，PD153035可延长维甲酸受体β mRNA的半衰期。PD153035不会上调其他维甲酸受体、雌激素受体α或RASSF1A。因此，PD153035通过不依赖ErbB的转录和转录后机制诱导维甲酸受体β。本报告突出了一种ErbB-1抑制剂的三重作用（抑制ErbB-1、插入DNA、诱导维甲酸受体β）。这种多靶点药物在癌症治疗方面具有巨大潜力。
