GFRA1 promotes cisplatin-induced chemoresistance in osteosarcoma by inducing autophagy
GFRA1 promotes cisplatin-induced chemoresistance in osteosarcoma by inducing autophagy
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DOI：
10.1080/15548627.2016.1239676
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发表时间：
2017-01-01
期刊：
影响因子：
13.3
通讯作者：
Kim, Dae Joon
中科院分区：
文献类型：
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作者：
Kim, Mihwa;Jung, Ji-Yeon;Kim, Dae Joon
化疗的最新进展显着提高了其疗效，但耐药性的发展仍然是一个主要的缺点。在这项研究中，我们发现GFRA 1/GFR 1（GDNF家族受体1），有助于顺铂诱导的化疗耐药，通过调节自噬骨肉瘤。我们证明，顺铂治疗诱导GFRA 1在人骨肉瘤细胞的表达。GFRA 1表达的诱导减少了顺铂诱导的细胞凋亡，并通过自噬显著增加了骨肉瘤细胞的存活。GFRA 1通过促进SRC磷酸化调节AMPK依赖性自噬，而不依赖于原癌基因RET激酶。顺铂耐药骨肉瘤细胞显示NFKB 1/NFB介导的GFRA 1表达。GFRA 1表达促进小鼠异种移植模型中的肿瘤形成和生长，并且在顺铂治疗期间抑制GFRA 1表达异种移植小鼠模型中的自噬有效地减少肿瘤生长并增加存活。在顺铂治疗的患者中，治疗期和转移状态与GFRA 1介导的自噬相关。这些发现表明GFRA 1介导的自噬是克服骨肉瘤顺铂耐药的一个有前途的新靶点。
Recent progress in chemotherapy has significantly increased its efficacy, yet the development of chemoresistance remains a major drawback. In this study, we show that GFRA1/GFR1 (GDNF family receptor 1), contributes to cisplatin-induced chemoresistance by regulating autophagy in osteosarcoma. We demonstrate that cisplatin treatment induced GFRA1 expression in human osteosarcoma cells. Induction of GFRA1 expression reduced cisplatin-induced apoptotic cell death and it significantly increased osteosarcoma cell survival via autophagy. GFRA1 regulates AMPK-dependent autophagy by promoting SRC phosphorylation independent of proto-oncogene RET kinase. Cisplatin-resistant osteosarcoma cells showed NFKB1/NFB-mediated GFRA1 expression. GFRA1 expression promoted tumor formation and growth in mouse xenograft models and inhibition of autophagy in a GFRA1-expressing xenograft mouse model during cisplatin treatment effectively reduced tumor growth and increased survival. In cisplatin-treated patients, treatment period and metastatic status were associated with GFRA1-mediated autophagy. These findings suggest that GFRA1-mediated autophagy is a promising novel target for overcoming cisplatin resistance in osteosarcoma.