Role of FBXW7 in the quiescence of gefitinib-resistant lung cancer stem cells in EGFR-mutant non-small cell lung cancer

  • Moulid Hidayat Department of Respiratory Medicine; Research Institute for Diseases of Old Ages, Graduate School of Medicine, Juntendo University, Tokyo, Japan https://orcid.org/0000-0001-5526-2700
  • Yoichiro Mitsuishi Department of Respiratory Medicine; Research Institute for Diseases of Old Ages, Graduate School of Medicine, Juntendo University, Tokyo, Japan https://orcid.org/0000-0001-7040-6653
  • Fumiyuki Takahashi Department of Respiratory Medicine; Research Institute for Diseases of Old Ages, Graduate School of Medicine, Juntendo University, Tokyo, Japan
  • Ken Tajima Department of Respiratory Medicine; Research Institute for Diseases of Old Ages, Graduate School of Medicine, Juntendo University, Tokyo, Japan
  • Toshifumi Yae Department of Respiratory Medicine; Research Institute for Diseases of Old Ages, Graduate School of Medicine, Juntendo University, Tokyo, Japan https://orcid.org/0000-0002-0077-9857
  • Katsumi Miyahara Laboratory of Morphology and Image Analysis, Research Support Center, Graduate School of Medicine, Juntendo University, Tokyo, Japan https://orcid.org/0000-0001-7492-2524
  • Daisuke Hayakawa Department of Respiratory Medicine; Research Institute for Diseases of Old Ages, Graduate School of Medicine, Juntendo University, Tokyo, Japan https://orcid.org/0000-0002-2116-5264
  • Wira Winardi Department of Respiratory Medicine; Research Institute for Diseases of Old Ages, Graduate School of Medicine, Juntendo University, Tokyo, Japan https://orcid.org/0000-0002-0880-7445
  • Hiroaki Ihara Department of Respiratory Medicine; Research Institute for Diseases of Old Ages, Graduate School of Medicine, Juntendo University, Tokyo, Japan
  • Yoshika Koinuma Department of Respiratory Medicine; Research Institute for Diseases of Old Ages, Graduate School of Medicine, Juntendo University, Tokyo, Japan
  • Aditya Wirawan Department of Respiratory Medicine; Research Institute for Diseases of Old Ages, Graduate School of Medicine, Juntendo University, Tokyo, Japan https://orcid.org/0000-0002-0110-7809
  • Fariz Nurwidya Department of Respiratory Medicine; Research Institute for Diseases of Old Ages, Graduate School of Medicine, Juntendo University, Tokyo, Japan https://orcid.org/0000-0002-8379-9510
  • Motoyasu Kato Department of Respiratory Medicine; Research Institute for Diseases of Old Ages, Graduate School of Medicine, Juntendo University, Tokyo, Japan https://orcid.org/0000-0002-3217-5118
  • Isao Kobayashi Department of Respiratory Medicine; Research Institute for Diseases of Old Ages, Graduate School of Medicine, Juntendo University, Tokyo, Japan https://orcid.org/0000-0002-3908-4681
  • Shinichi Sasaki Department of Respiratory Medicine; Research Institute for Diseases of Old Ages, Graduate School of Medicine, Juntendo University, Tokyo, Japan
  • Kazuya Takamochi Department of General Thoracic Surgery, Graduate School of Medicine, Juntendo University, Tokyo, Japan
  • Takuo Hayashi Department of Human Pathology, Graduate School of Medicine, Juntendo University, Tokyo, Japan
  • Yoshiyuki Suehara Department of Orthopedic Surgery, Graduate School of Medicine, Juntendo University, Tokyo, Japan https://orcid.org/0000-0001-8206-3037
  • Mariko Moriyama Pharmaceutical Research and Technology Institute, School of Medicine, Kinki University, Osaka, Japan https://orcid.org/0000-0003-1277-1841
  • Hiroyuki Moriyama Pharmaceutical Research and Technology Institute, School of Medicine, Kinki University, Osaka, Japan https://orcid.org/0000-0001-7558-1063
  • Sonoko Habu Research Institute for Diseases of Old Ages, Graduate School of Medicine, Juntendo University, Tokyo; Atopic Research Center, Graduate School of Medicine, Juntendo University, Tokyo, Japan https://orcid.org/0000-0003-4338-932X
  • Kazuhisa Takahashi Department of Respiratory Medicine; Research Institute for Diseases of Old Ages, Graduate School of Medicine, Juntendo University, Tokyo, Japan
Keywords: FBXW7, quiescence, cancer stem cells, gefitinib resistance, NSCLC

Abstract

Several recent studies suggest that cancer stem cells (CSCs) are involved in intrinsic resistance to cancer treatment. Maintenance of quiescence is crucial for establishing resistance of CSCs to cancer therapeutics. F-box/WD repeat-containing protein 7 (FBXW7) is a ubiquitin ligase that regulates quiescence by targeting the c-MYC protein for ubiquitination. We previously reported that gefitinib-resistant persisters (GRPs) in EGFR-mutant non-small cell lung cancer (NSCLC) cells highly expressed octamer-binding transcription factor 4 (Oct-4) as well as the lung CSC marker CD133, and they exhibited distinctive features of the CSC phenotype. However, the role of FBXW7 in lung CSCs and their resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors in NSCLC is not fully understood. In this study, we developed GRPs from the two NSCLC cell lines PC9 and HCC827, which express an EGFR exon 19 deletion mutation, by treatment with a high concentration of gefitinib. The GRPs from both PC9 and HCC827 cells expressed high levels of CD133 and FBXW7, but low levels of c-MYC. Cell cycle analysis demonstrated that the majority of GRPs existed in the G0/G1 phase. Knockdown of the FBXW7 gene significantly reduced the cell number of CD133-positive GRPs and reversed the cell population in the G0/G1-phase. We also found that FBXW7 expression in CD133-positive cells was increased and c-MYC expression was decreased in gefitinib-resistant tumors of PC9 cells in mice and in 9 out of 14 tumor specimens from EGFR-mutant NSCLC patients with acquired resistance to gefitinib. These findings suggest that FBXW7 plays a pivotal role in the maintenance of quiescence in gefitinib-resistant lung CSCs in EGFR mutation-positive NSCLC.

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Role of FBXW7 in the quiescence of gefitinib-resistant lung cancer stem cells in EGFR-mutant non-small cell lung cancer
Published
2019-11-08
How to Cite
1.
Hidayat M, Mitsuishi Y, Takahashi F, Tajima K, Yae T, Miyahara K, Hayakawa D, Winardi W, Ihara H, Koinuma Y, Wirawan A, Nurwidya F, Kato M, Kobayashi I, Sasaki S, Takamochi K, Hayashi T, Suehara Y, Moriyama M, Moriyama H, Habu S, Takahashi K. Role of FBXW7 in the quiescence of gefitinib-resistant lung cancer stem cells in EGFR-mutant non-small cell lung cancer. Bosn J of Basic Med Sci [Internet]. 2019Nov.8 [cited 2019Nov.12];19(4):355-67. Available from: https://bjbms.org/ojs/index.php/bjbms/article/view/4227
Section
Molecular Biology