GFRA1 promotes cisplatin-induced chemoresistance in osteosarcoma by inducing autophagy |
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| Authors: | Mihwa Kim Ji-Yeon Jung Seungho Choi Hyunseung Lee Liza D. Morales Jeong-Tae Koh |
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| Affiliation: | 1. Department of Oral Physiology, School of Dentistry, Chonnam National University, Gwangju, Korea;2. Edinburg Regional Academic Health Center, Medical Research Division, University of Texas Health Science Center at San Antonio, Edinburg, TX, USA;3. Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA;4. Dental Science Research Institute, Medical Research Center for Biomineralization Disorders, School of Dentistry, Chonnam National University, Gwangju, Korea;5. Edinburg Regional Academic Health Center, Medical Research Division, University of Texas Health Science Center at San Antonio, Edinburg, TX, USA;6. Dental Science Research Institute, Medical Research Center for Biomineralization Disorders, School of Dentistry, Chonnam National University, Gwangju, Korea;7. Department of Pharmacology and Dental Therapeutics, School of Dentistry, Chonnam National University, Gwangju, Korea |
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| Abstract: | 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. |
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| Keywords: | AMPK autophagy chemoresistance GFRA1 osteosarcoma SRC |
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