NSC-87877 inhibits DUSP26 function in neuroblastoma resulting in p53-mediated apoptosis.
NSC-87877 inhibits DUSP26 function in neuroblastoma resulting in p53-mediated apoptosis.
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DOI：
10.1038/cddis.2015.207
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发表时间：
2015-08-06
影响因子：
9
通讯作者：
Yang J
中科院分区：
文献类型：
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作者：
Shi Y;Ma IT;Patel RH;Shang X;Chen Z;Zhao Y;Cheng J;Fan Y;Rojas Y;Barbieri E;Chen Z;Yu Y;Jin J;Kim ES;Shohet JM;Vasudevan SA;Yang J
双特异性蛋白磷酸酶26（DUSP 26）在高危神经母细胞瘤（NB）中过表达，并通过抑制p53功能导致化疗耐药。在体外，DUSP 26还显示出有效抑制p38 MAP激酶。我们假设抑制DUSP 26将导致NB细胞生长以p53和/或p38介导的方式减少。NSC-87877（8-羟基-7-[（6-磺基-2-萘基）偶氮]-5-喹啉磺酸）是一种新型DUSP 26小分子抑制剂，在NB细胞系中显示出有效的生长抑制和凋亡诱导作用。用靶向DUSP 26的小发夹RNA（shRNA）处理的NB细胞系在体外和体内也表现出增殖缺陷。用NSC-87877处理NB细胞系导致p53磷酸化（Ser 37和Ser 46）和活化增加，下游p38效应蛋白（热休克蛋白27（HSP 27）和MAP激酶活化的蛋白激酶2（MAPKAPK 2））的活化增加以及聚ADP核糖聚合酶/半胱天冬酶-3切割增加。通过用shRNA敲低p53表达以及通过用SB 203580（4-[4-（4-氟苯基）-2-（4-甲基亚磺酰基苯基）-1H-咪唑-5-基]吡啶）抑制p38活性，部分逆转了DUSP 26抑制产生的细胞毒性。在NB的肾内小鼠模型中，NSC-87877治疗导致肿瘤生长减少和p53和p38活性增加。总之，这些结果表明，使用NSC-87877抑制DUSP 26是通过激活p53和p38丝裂原活化蛋白激酶（MAPK）肿瘤抑制途径在体外和体内诱导NB细胞毒性的有效策略。
Dual specificity protein phosphatase 26 (DUSP26) is overexpressed in high-risk neuroblastoma (NB) and contributes to chemoresistance by inhibiting p53 function. In vitro, DUSP26 has also been shown to effectively inhibit p38 MAP kinase. We hypothesize that inhibiting DUSP26 will result in decreased NB cell growth in a p53 and/or p38-mediated manner. NSC-87877 (8-hydroxy-7-[(6-sulfo-2-naphthyl)azo]-5-quinolinesulfonic acid), a novel DUSP26 small molecule inhibitor, shows effective growth inhibition and induction of apoptosis in NB cell lines. NB cell lines treated with small hairpin RNA (shRNA) targeting DUSP26 also exhibit a proliferation defect both in vitro and in vivo. Treatment of NB cell lines with NSC-87877 results in increased p53 phosphorylation (Ser37 and Ser46) and activation, increased activation of downstream p38 effector proteins (heat shock protein 27 (HSP27) and MAP kinase-activated protein kinase 2 (MAPKAPK2)) and poly ADP ribose polymerase/caspase-3 cleavage. The cytotoxicity resulting from DUSP26 inhibition is partially reversed by knocking down p53 expression with shRNA and also by inhibiting p38 activity with SB203580 (4-[4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-1H-imidazol-5-yl]pyridine). In an intrarenal mouse model of NB, NSC-87877 treatment results in decreased tumor growth and increased p53 and p38 activity. Together, these results suggest that DUSP26 inhibition with NSC-87877 is an effective strategy to induce NB cell cytotoxicity in vitro and in vivo through activation of the p53 and p38 mitogen-activated protein kinase (MAPK) tumor-suppressor pathways.