title: GFRA1 promotes cisplatin-induced chemoresistance in osteosarcoma by inducing autophagy.
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.
authors.affiliation: 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.|c Department of Pharmacology , University of Texas Health Science Center at San Antonio , San Antonio , TX , USA.
authors.forename: Mihwa
authors.initials: M
authors.lastname: Kim
authors.affiliation: a Department of Oral Physiology , School of Dentistry, Chonnam National University , Gwangju , Korea.|d Dental Science Research Institute , Medical Research Center for Biomineralization Disorders, School of Dentistry, Chonnam National University , Gwangju , Korea.
authors.forename: Ji-Yeon
authors.initials: JY
authors.lastname: Jung
authors.affiliation: a Department of Oral Physiology , School of Dentistry, Chonnam National University , Gwangju , Korea.
authors.forename: Seungho
authors.initials: S
authors.lastname: Choi
authors.affiliation: b Edinburg Regional Academic Health Center, Medical Research Division, University of Texas Health Science Center at San Antonio , Edinburg , TX , USA.|c Department of Pharmacology , University of Texas Health Science Center at San Antonio , San Antonio , TX , USA.
authors.forename: Hyunseung
authors.initials: H
authors.lastname: Lee
authors.affiliation: b Edinburg Regional Academic Health Center, Medical Research Division, University of Texas Health Science Center at San Antonio , Edinburg , TX , USA.
authors.forename: Liza D
authors.initials: LD
authors.lastname: Morales
authors.affiliation: d Dental Science Research Institute , Medical Research Center for Biomineralization Disorders, School of Dentistry, Chonnam National University , Gwangju , Korea.|e Department of Pharmacology and Dental Therapeutics , School of Dentistry, Chonnam National University , Gwangju , Korea.
authors.forename: Jeong-Tae
authors.initials: JT
authors.lastname: Koh
authors.affiliation: d Dental Science Research Institute , Medical Research Center for Biomineralization Disorders, School of Dentistry, Chonnam National University , Gwangju , Korea.|f Department of Oral Anatomy, School of Dentistry , Chonnam National University , Gwangju , Korea.
authors.forename: Sun Hun
authors.initials: SH
authors.lastname: Kim
authors.affiliation: g Department of Pathology , Chonnam National University Medical School , Gwangju , Korea.
authors.forename: Yoo-Duk
authors.initials: YD
authors.lastname: Choi
authors.affiliation: g Department of Pathology , Chonnam National University Medical School , Gwangju , Korea.
authors.forename: Chan
authors.initials: C
authors.lastname: Choi
authors.affiliation: c Department of Pharmacology , University of Texas Health Science Center at San Antonio , San Antonio , TX , USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Slaga
authors.affiliation: a Department of Oral Physiology , School of Dentistry, Chonnam National University , Gwangju , Korea.|d Dental Science Research Institute , Medical Research Center for Biomineralization Disorders, School of Dentistry, Chonnam National University , Gwangju , Korea.
authors.forename: Won Jae
authors.initials: WJ
authors.lastname: Kim
authors.affiliation: b Edinburg Regional Academic Health Center, Medical Research Division, University of Texas Health Science Center at San Antonio , Edinburg , TX , USA.|c Department of Pharmacology , University of Texas Health Science Center at San Antonio , San Antonio , TX , USA.
authors.forename: Dae Joon
authors.initials: DJ
authors.lastname: Kim
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D041681:NIH 3T3 Cells; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D012516:Osteosarcoma / Q000188:drug therapy* / Q000378:metabolism; D010766:Phosphorylation; D000090063:Proto-Oncogene Mas; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation
chemical_list: C494987:GFRA1 protein, human; C494988:Gfra1 protein, mouse; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D034741:RNA, Small Interfering; D055372:AMP-Activated Protein Kinases; D002945:Cisplatin
keywords: AMPK; GFRA1; SRC; autophagy; chemoresistance; osteosarcoma