All trans-retinoic acid analogs promote cancer cell apoptosis through non-genomic Crabp1 mediating ERK1/2 phosphorylation.
All trans-retinoic acid analogs promote cancer cell apoptosis through non-genomic Crabp1 mediating ERK1/2 phosphorylation.
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DOI：
10.1038/srep22396
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发表时间：
2016-03-03
影响因子：
4.6
通讯作者：
Wei LN
中科院分区：
文献类型：
--
作者：
Persaud SD;Park SW;Ishigami-Yuasa M;Koyano-Nakagawa N;Kagechika H;Wei LN
全反式维甲酸（atRA）是目前最有效的抗肿瘤药物之一，但由于核维甲酸受体（RAR）的广泛毒性限制了其在临床上的应用。AtRA还发挥非基因组活动的机制仍然知之甚少。我们确定细胞视黄酸结合蛋白1（Crabp 1）介导atRA的非基因组活性，并确定两种化合物作为Crabp 1的配体，以快速和RAR独立地激活细胞外信号调节激酶1/2（ERK 1/2）。在胚胎干细胞（ESC）中，非离子激活的ERK激活蛋白磷酸酶2A（PP 2A）并延长细胞周期持续时间。这在Crabp 1-null ESC中被废除。在Crabp 1阴性癌细胞中重新表达Crabp 1也使atRA诱导的凋亡敏感。这项研究揭示了由Crabp 1介导的atRA的非基因组作用在调节细胞周期进展和凋亡诱导中的生理相关性，并提供了一种新的癌症治疗策略，其中特异性靶向Crabp 1的化合物可以以不依赖于RAR的方式调节细胞周期和癌细胞凋亡，从而避免atRA的毒性由其基因组效应引起。
All trans retinoic acid (atRA) is one of the most potent therapeutic agents, but extensive toxicity caused by nuclear RA receptors (RARs) limits its clinical application in treating cancer. AtRA also exerts non-genomic activities for which the mechanism remains poorly understood. We determine that cellular retinoic acid binding protein 1 (Crabp1) mediates the non-genomic activity of atRA, and identify two compounds as the ligands of Crabp1 to rapidly and RAR-independently activate extracellular signal regulated kinase 1/2 (ERK1/2). Non-canonically activated ERK activates protein phosphatase 2A (PP2A) and lengthens cell cycle duration in embryonic stem cells (ESC). This is abolished in Crabp1-null ESCs. Re-expressing Crabp1 in Crabp1-negative cancer cells also sensitizes their apoptotic induction by atRA. This study reveals a physiological relevance of the non-genomic action of atRA, mediated by Crabp1, in modulating cell cycle progression and apoptosis induction, and provides a new cancer therapeutic strategy whereby compounds specifically targeting Crabp1 can modulate cell cycle and cancer cell apoptosis in a RAR-independent fashion, thereby avoiding atRA’s toxicity caused by its genomic effects.