Journal
AUTOPHAGY
Volume 13, Issue 1, Pages 149-168Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/15548627.2016.1239676
Keywords
AMPK; autophagy; chemoresistance; GFRA1; osteosarcoma; SRC
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Funding
- Edinburg Regional Academic Health Center, University of Texas Health Science Center at San Antonio
- National Institutes of Health, NIEHS [ES022250]
- National Research Foundation of Korea [2010-0004810]
- National Research Foundation of Korea (NRF) - Korea government MSIP [2011-0030121, 20141A2A2A01007582]
- MSIP [2015R1A2A2A01006595]
- National Research Foundation of Korea [2010-0004810] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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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.
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