Autophagy is associated with chemoresistance in neuroblastoma.
Autophagy is associated with chemoresistance in neuroblastoma.
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自噬与神经母细胞瘤的化学抗性有关。
DOI：
10.1186/s12885-016-2906-9
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发表时间：
2016-11-15
期刊：
影响因子：
3.8
通讯作者：
Sartelet H
中科院分区：
文献类型：
--
作者：
Belounis A;Nyalendo C;Le Gall R;Imbriglio TV;Mahma M;Teira P;Beaunoyer M;Cournoyer S;Haddad E;Vassal G;Sartelet H
神经母细胞瘤(NB)是一种常见的儿科肿瘤，其特点是预后较差，大多数肿瘤在强化综合治疗的情况下仍有进展。自噬是细胞中的一种自我降解过程，化疗可以诱导自噬，并与化疗耐药有关。这项研究的目的是确定：1)自噬是否存在于NB中，2)化疗是否改变了自噬的水平，3)抑制自噬是否降低了化疗耐药性。应用免疫组织化学方法检测184例神经母细胞瘤标本中自噬特异性标记物LC3B和自噬阳性调节因子Beclin 1的表达。此外，我们还对6个NB细胞株和6种药物(长春新碱、阿霉素、顺铂、替莫唑胺、LY294002和赛罗莫司)进行了体外研究。用ATG5基因敲除细胞或羟基氯喹(HCQ)抑制自噬。用四甲基偶氮唑盐比色法测定细胞存活率。用单丹西林、共聚焦显微镜和Western印迹检测细胞自噬。对NSG小鼠进行了体内移植瘤的研究。我们的结果表明，自噬在NB中低水平存在，不是一个预后因素，而Beclin 1在预后不良的儿童中高表达。然而，在体外和体内化疗后，自噬水平增加。HCQ和长春新碱联合治疗的小鼠肿瘤进展显著减少。综上所述，在NB中存在自噬，由化疗诱导，并与化疗耐药相关，这种自噬通过抑制显著减少。因此，靶向自噬是一种非常有吸引力的方法来开发新的治疗策略。本文的在线版本(doi：10.1186/s12885-0162906-9)包含补充材料，授权用户可以使用。
Neuroblastoma (NB) is a frequent pediatric tumor characterized by a poor prognosis where a majority of tumors progress despite intensive multimodality treatments. Autophagy, a self-degradative process in cells, could be induced by chemotherapy and be associated with chemoresistance. The aim of this study was to determine whether: 1) autophagy is present in NB, 2) chemotherapy modified its levels, and 3) its inhibition decreased chemoresistance. Immunohistochemical stainings were performed on samples from 184 NB patients in order to verify the expression of LC3B, a specific marker for autophagy, and Beclin 1, a positive regulator of autophagy. In addition, we performed an in vitro study with six NB cell lines and six drugs (vincristine, doxorubicin, cisplatin temozolomide, LY294002 and syrolimus). Inhibition of autophagy was performed using ATG5 knockdown cells or hydroxychloroquine (HCQ). Cell survival was measured using the MTT cell proliferation assay. Autophagy was detected by monodansylcadaverine, confocal microscopy and Western blot. In vivo study with tumor xenografts in NSG mice was performed. Our results have indicated that autophagy was present at low levels in NB and was not a prognostic factor, while Beclin 1 was highly expressed in children with poor NB prognosis. However, autophagy levels increased after chemotherapy in vitro and in vivo. Tumor progression was significantly decreased in mice treated with a combination of HCQ and vincristine. Taken together, autophagy is present in NB, induced by chemotherapy and associated with chemoresistance, which is significantly reduced by its inhibition. Therefore, targeting autophagy represents a very attractive approach to develop new therapeutic strategies in NB. The online version of this article (doi:10.1186/s12885-016-2906-9) contains supplementary material, which is available to authorized users.
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影响因子：
11.1
作者：
He C;Klionsky DJ
通讯作者：
Klionsky DJ
影响因子：
11.5
作者：
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影响因子：
158.5
作者：
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