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全反式维甲酸治疗白血病关键靶点

来源:生物谷 2015-04-20 11:55

                                                                      

2015年4月20日讯 /生物谷BIOON/ --近日,来自美国哈佛大学医学院的研究人员在国际学术期刊nature medicine在线发表了一项最新研究成果,他们发现急性早幼粒白血病治疗药物--全反式维甲酸主要以异构酶Pin1为作用靶点,在癌细胞中抑制并促进Pin1降解,并对其中的机制进行了深入探讨。
 
异构酶Pin1是多种癌症类型中致癌信号通路的共同关键调控因子。但是目前的Pin1抑制剂都缺少特异性,并且对于pin1功能的抑制不够强力。在该项研究中,研究人员通过筛选,发现全反式维甲酸(ATRA)能够在癌细胞中特异性抑制并降解Pin1,并且全反式维甲酸的这种抑制作用是通过直接结合Pin1活性位点中的底物磷酸和脯氨酸结合口袋实现的。
 
全反式维甲酸是一种治疗急性早幼粒白血病的治疗药物,一直以来,ATRA一直被当作第一个靶向治疗癌症的例子,但其药物靶点一直不清楚。研究人员发现,ATRA诱导的Pin1消除会降解融合癌基因PML-RARA编码的蛋白,并且在APL细胞,动物模型和APL病人中都得到了验证。ATRA诱导的Pin1消除也强烈抑制了三隐形乳腺癌细胞的生长,并且这种作用是通过影响Pin1底物中的癌基因和肿瘤抑制因子表达实现的。
 
因此,该研究发现ATRA能够同时阻断多条Pin1调节的致癌信号通路,对于治疗恶性肿瘤和对化疗药物抵抗的肿瘤具有重要意义。(生物谷Bioon.com)
 
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Active Pin1 is a key target of all-trans retinoic acid in acute promyelocytic leukemia and breast cancer
 
Shuo Wei,Shingo Kozono,Lev Kats,Morris Nechama,Wenzong Li,Jlenia Guarnerio,Manli Luo,Mi-Hyeon You,Yandan Yao,Asami Kondo,Hai Hu,Gunes Bozkurt,Nathan J Moerke,Shugeng Cao,Markus Reschke,Chun-Hau Chen,Eduardo M Rego,Francesco Lo-Coco,Lewis C Cantley,Tae Ho Lee,Hao Wu,Yan Zhang,Pier Paolo Pandolfi,Xiao Zhen Zhou & Kun Ping Lu
 
A common key regulator of oncogenic signaling pathways in multiple tumor types is the unique isomerase Pin1. However, available Pin1 inhibitors lack the required specificity and potency for inhibiting Pin1 function in vivo. By using mechanism-based screening, here we find that all-transretinoic acid (ATRA)-a therapy for acute promyelocytic leukemia (APL) that is considered the first example of targeted therapy in cancer, but whose drug target remains elusive-inhibits and degrades active Pin1 selectively in cancer cells by directly binding to the substrate phosphate- and proline-binding pockets in the Pin1 active site. ATRA-induced Pin1 ablation degrades the protein encoded by the fusion oncogene PML-RARA and treats APL in APL cell and animal models as well as in human patients. ATRA-induced Pin1 ablation also potently inhibits triple-negative breast cancer cell growth in human cells and in animal models by acting on many Pin1 substrate oncogenes and tumor suppressors. Thus, ATRA simultaneously blocks multiple Pin1-regulated cancer-driving pathways, an attractive property for treating aggressive and drug-resistant tumors.
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