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Cancer res:维甲酸治疗癌症失效的根本原因

来源:生物谷 2014-08-15 18:13

2014年8月15日讯 /生物谷BIOON/--维甲酸是维生素A的一种形式,主要用于治疗癌症,有助于预防多种癌症的复发,但某些患者用药后效果不佳。

某些癌症患者出现抵抗药物治疗的原因尚不明确,但近日Virginia Commonwealth University (VCU) Massey Cancer Center研究人员发现实际上,一种蛋白AEG-1阻断,维甲酸对白血病和肝癌的治疗作用。由于AEG-1在几乎所有的癌症中都过度表达,因此这些研究结果可能会影响无数癌症病人的结果。

这项研究结论发表在Cancer Research杂志上。Devanand Sarkar博士领导的研究小组表明,蛋白质AEG-1与维甲酸X受体(RXR)结合(维甲酸X受体帮助调节细胞的生长),阻断了维甲酸治疗癌症的效益。RXR通常由维甲酸激活,但在肿瘤细胞中发现,过表达的AEG-1蛋白会阻断这些信号,并帮助促进肿瘤生长。使用复杂的动物模型,研究人员发现,阻断AEG-1的生成能再次使得维甲酸能杀死肝癌细胞。

Sarkar说:研究结果首次揭示了AEG-1与维甲酸X受体的相互作用。这项研究具有直接的临床相关性,使得医生可以开始根据筛选癌症患者AEG-1表达水平,以确定是否给予患者维甲酸。

Sarkar和他的同事们多年来一直在研究AEG-1。他们最早利用了小鼠模型证实AEG-1在肝癌中的作用,并积极开展有针对性的治疗方法,以阻止AEG-1的生成。(生物谷Bioon.com)

AEG-1 Regulates Retinoid X Receptor and Inhibits Retinoid Signaling

Jyoti Srivastava,et al.

Retinoid X receptor (RXR) regulates key cellular responses such as cell growth and development, and this regulation is frequently perturbed in various malignancies, including hepatocellular carcinoma (HCC). However, the molecule(s) that physically govern this deregulation are mostly unknown. Here, we identified RXR as an interacting partner of astrocyte-elevated gene-1 (AEG-1)/metadherin (MTDH), an oncogene upregulated in all cancers. Upon interaction, AEG-1 profoundly inhibited RXR/retinoic acid receptor (RAR)–mediated transcriptional activation. Consequently, AEG-1 markedly protected HCC and acute myelogenous leukemia (AML) cells from retinoid- and rexinoid-induced cell death. In nontumorigenic cells and primary hepatocytes, AEG-1/RXR colocalizes in the nucleus in which AEG-1 interferes with recruitment of transcriptional coactivators to RXR, preventing transcription of target genes. In tumor cells and AEG-1 transgenic hepatocytes, overexpressed AEG-1 entraps RXR in cytoplasm, precluding its nuclear translocation. In addition, ERK, activated by AEG-1, phosphorylates RXR that leads to its functional inactivation and attenuation of ligand-dependent transactivation. In nude mice models, combination of all-trans retinoic acid (ATRA) and AEG-1 knockdown synergistically inhibited growth of human HCC xenografts. The present study establishes AEG-1 as a novel homeostatic regulator of RXR and RXR/RAR that might contribute to hepatocarcinogenesis. Targeting AEG-1 could sensitize patients with HCC and AML to retinoid- and rexinoid-based therapeutics..

 

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