a Department of Oral Physiology , School of Dentistry, Chonnam National University , Gwangju , Korea.
b Edinburg Regional Academic Health Center, Medical Research Division, University of Texas Health Science Center at San Antonio , Edinburg , TX , USA.
Autophagy. 2017 Jan 2;13(1):149-168. doi: 10.1080/15548627.2016.1239676. Epub 2016 Oct 18.
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/GFRα1 (GDNF family receptor α 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/NFκB-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.
最近在化疗方面的进展显著提高了其疗效，但化疗耐药性的发展仍然是一个主要的缺点。在这项研究中，我们表明 GFRA1/GFRα1（GDNF 家族受体 α1）通过调节骨肉瘤中的自噬作用，导致顺铂诱导的化疗耐药性。我们证明顺铂处理诱导人骨肉瘤细胞中 GFRA1 的表达。GFRA1 表达的诱导降低了顺铂诱导的细胞凋亡死亡，并且通过自噬显著增加了骨肉瘤细胞的存活。GFRA1 通过促进 SRC 磷酸化而不依赖原癌基因 RET 激酶来调节 AMPK 依赖性自噬。顺铂耐药骨肉瘤细胞表现出 NFKB1/NFκB 介导的 GFRA1 表达。GFRA1 表达促进了在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在表达 GFRA1 的异种移植小鼠模型中抑制自噬有效地减少了肿瘤生长并增加了存活率。在接受顺铂治疗的患者中，治疗期和转移性状态与 GFRA1 介导的自噬有关。这些发现表明，GFRA1 介导的自噬是克服骨肉瘤中顺铂耐药性的有前途的新靶点。
