Sensitization of osteosarcoma to irradiation by targeting nuclear FGFR1

Jin Ah Kim, Noah E. Berlow, Melvin Lathara, Narendra Bharathy, Leah R. Martin, Reshma Purohit, Megan M. Cleary, Qianqian Liu, Joel E. Michalek, Ganapati Srinivasa, Bonnie L. Cole, Sonja D. Chen, Charles Keller

Research output: Contribution to journalArticlepeer-review

Abstract

Over the past 25 years, chemotherapy regimens for osteosarcoma have failed to improve the 65–70% long-term survival rate. Radiation therapy is generally ineffective except for palliative care. We here investigated whether osteosarcoma can be sensitized to radiation therapy targeting specific molecules in osteosarcoma. Large-scale RNA sequencing analysis in osteosarcoma tissues and cell lines revealed that FGFR1 is the most frequently expressed receptor tyrosine kinase in osteosarcoma. Nuclear FGFR1 (nFGFR1) was observed by subcellular localization assays. The functional studies using a FGFR1IIIb antibody or small molecule FGFR1 inhibitors showed that nFGFR1, but not membrane-bound FGFR1, induces G2 cell-cycle checkpoint adaptation, cell survival and polyploidy following irradiation in osteosarcoma cells. Further, the activation of nFGFR1 induces Histone H3 phosphorylation at Ser 10 and c-jun/c-fos expression to contribute cell survival rendering radiation resistance. Furthermore, an in vivo mouse study revealed that radiation resistance can be reversed by the inhibition of nFGFR1. Our findings provide insights into the potential role of nFGFR1 to radiation resistance. Thus, we propose nFGFR1 could be a potential therapeutic target or a biomarker to determine which patients might benefit from radiation therapy.

Original languageEnglish (US)
Pages (from-to)101-108
Number of pages8
JournalBiochemical and Biophysical Research Communications
Volume621
DOIs
StatePublished - Sep 17 2022

Keywords

  • Cell survival
  • G2 checkpoint adaptation
  • Histone modification
  • Nuclear FGFR1
  • Osteosarcoma
  • Radiation resistance
  • c-Jun/c-Fos expression

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint

Dive into the research topics of 'Sensitization of osteosarcoma to irradiation by targeting nuclear FGFR1'. Together they form a unique fingerprint.

Cite this