Kim, Mihwa Jung, Ji-Yeon Choi, Seungho Lee, Hyunseung D. Morales, Liza Koh, Jeong-Tae Kim, Sun Hun Choi, Yoo-Duk Choi, Chan Slaga, Thomas J. Kim, Won Jae Joon Kim, Dae GFRA1 promotes cisplatin-induced chemoresistance in osteosarcoma by inducing autophagy <p>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 <i>RET</i> 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.</p> AMPK;autophagy;chemoresistance;GFRA1;osteosarcoma;SRC 2016-11-10
    https://tandf.figshare.com/articles/dataset/GFRA1_Promotes_Cisplatin-induced_Chemoresistance_in_Osteosarcoma_by_Inducing_Autophagy/4039986
10.6084/m9.figshare.4039986.v2