GFRA1 promotes cisplatin-induced chemoresistance in osteosarcoma by inducing autophagy

Mihwa Kim, Ji Yeon Jung, Seungho Choi, Hyunseung Lee, Liza D. Morales, Jeong Tae Koh, Sun Hun Kim, Yoo Duk Choi, Chan Choi, Thomas J. Slaga, Won Jae Kim, Dae Joon Kim

Research output: Contribution to journalArticle

59 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)149-168
Number of pages20
JournalAutophagy
Volume13
Issue number1
DOIs
StatePublished - Jan 2 2017

Keywords

  • AMPK
  • GFRA1
  • SRC
  • autophagy
  • chemoresistance
  • osteosarcoma

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Kim, M., Jung, J. Y., Choi, S., Lee, H., Morales, L. D., Koh, J. T., Kim, S. H., Choi, Y. D., Choi, C., Slaga, T. J., Kim, W. J., & Kim, D. J. (2017). GFRA1 promotes cisplatin-induced chemoresistance in osteosarcoma by inducing autophagy. Autophagy, 13(1), 149-168. https://doi.org/10.1080/15548627.2016.1239676