Role of FBXW7 in the quiescence of gefitinib-resistant lung cancer stem cells in EGFR-mutant non-small cell lung cancer
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 q...
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Association of Basic Medical Sciences of Federation of Bosnia and Herzegovina
2019-05-01
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Series: | Bosnian Journal of Basic Medical Sciences |
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Online Access: | http://www.bjbms.org/ojs/index.php/bjbms/article/view/4227 |
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Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Moulid Hidayat Yoichiro Mitsuishi Fumiyuki Takahashi Ken Tajima Toshifumi Yae Katsumi Miyahara Daisuke Hayakawa Wira Winardi Hiroaki Ihara Yoshika Koinuma Aditya Wirawan Fariz Nurwidya Motoyasu Kato Isao Kobayashi Shinichi Sasaki Kazuya Takamochi Takuo Hayashi Yoshiyuki Suehara Mariko Moriyama Hiroyuki Moriyama Sonoko Habu Kazuhisa Takahashi |
spellingShingle |
Moulid Hidayat Yoichiro Mitsuishi Fumiyuki Takahashi Ken Tajima Toshifumi Yae Katsumi Miyahara Daisuke Hayakawa Wira Winardi Hiroaki Ihara Yoshika Koinuma Aditya Wirawan Fariz Nurwidya Motoyasu Kato Isao Kobayashi Shinichi Sasaki Kazuya Takamochi Takuo Hayashi Yoshiyuki Suehara Mariko Moriyama Hiroyuki Moriyama Sonoko Habu Kazuhisa Takahashi Role of FBXW7 in the quiescence of gefitinib-resistant lung cancer stem cells in EGFR-mutant non-small cell lung cancer Bosnian Journal of Basic Medical Sciences FBXW7 quiescence cancer stem cells gefitinib resistance NSCLC |
author_facet |
Moulid Hidayat Yoichiro Mitsuishi Fumiyuki Takahashi Ken Tajima Toshifumi Yae Katsumi Miyahara Daisuke Hayakawa Wira Winardi Hiroaki Ihara Yoshika Koinuma Aditya Wirawan Fariz Nurwidya Motoyasu Kato Isao Kobayashi Shinichi Sasaki Kazuya Takamochi Takuo Hayashi Yoshiyuki Suehara Mariko Moriyama Hiroyuki Moriyama Sonoko Habu Kazuhisa Takahashi |
author_sort |
Moulid Hidayat |
title |
Role of FBXW7 in the quiescence of gefitinib-resistant lung cancer stem cells in EGFR-mutant non-small cell lung cancer |
title_short |
Role of FBXW7 in the quiescence of gefitinib-resistant lung cancer stem cells in EGFR-mutant non-small cell lung cancer |
title_full |
Role of FBXW7 in the quiescence of gefitinib-resistant lung cancer stem cells in EGFR-mutant non-small cell lung cancer |
title_fullStr |
Role of FBXW7 in the quiescence of gefitinib-resistant lung cancer stem cells in EGFR-mutant non-small cell lung cancer |
title_full_unstemmed |
Role of FBXW7 in the quiescence of gefitinib-resistant lung cancer stem cells in EGFR-mutant non-small cell lung cancer |
title_sort |
role of fbxw7 in the quiescence of gefitinib-resistant lung cancer stem cells in egfr-mutant non-small cell lung cancer |
publisher |
Association of Basic Medical Sciences of Federation of Bosnia and Herzegovina |
series |
Bosnian Journal of Basic Medical Sciences |
issn |
1512-8601 1840-4812 |
publishDate |
2019-05-01 |
description |
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.
|
topic |
FBXW7 quiescence cancer stem cells gefitinib resistance NSCLC |
url |
http://www.bjbms.org/ojs/index.php/bjbms/article/view/4227 |
work_keys_str_mv |
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doaj-7c7f999ba6334c4dac324a6a0b67ea322020-11-25T02:52:06ZengAssociation of Basic Medical Sciences of Federation of Bosnia and HerzegovinaBosnian Journal of Basic Medical Sciences1512-86011840-48122019-05-0110.17305/bjbms.2019.4227Role of FBXW7 in the quiescence of gefitinib-resistant lung cancer stem cells in EGFR-mutant non-small cell lung cancerMoulid Hidayat0Yoichiro Mitsuishi1Fumiyuki Takahashi2Ken Tajima 3Toshifumi Yae 4Katsumi Miyahara5Daisuke Hayakawa6Wira Winardi7Hiroaki Ihara 8Yoshika Koinuma9Aditya Wirawan10Fariz Nurwidya 11Motoyasu Kato 12Isao Kobayashi13Shinichi Sasaki14Kazuya Takamochi15Takuo Hayashi16Yoshiyuki Suehara17Mariko Moriyama18Hiroyuki Moriyama19Sonoko Habu 20Kazuhisa Takahashi21Department of Respiratory Medicine; Research Institute for Diseases of Old Ages, Graduate School of Medicine, Juntendo University, Tokyo, JapanDepartment of Respiratory Medicine; Research Institute for Diseases of Old Ages, Graduate School of Medicine, Juntendo University, Tokyo, JapanDepartment of Respiratory Medicine; Research Institute for Diseases of Old Ages, Graduate School of Medicine, Juntendo University, Tokyo, JapanDepartment of Respiratory Medicine; Research Institute for Diseases of Old Ages, Graduate School of Medicine, Juntendo University, Tokyo, JapanDepartment of Respiratory Medicine; Research Institute for Diseases of Old Ages, Graduate School of Medicine, Juntendo University, Tokyo, JapanLaboratory of Morphology and Image Analysis, Research Support Center, Graduate School of Medicine, Juntendo University, Tokyo, JapanDepartment of Respiratory Medicine; Research Institute for Diseases of Old Ages, Graduate School of Medicine, Juntendo University, Tokyo, JapanDepartment of Respiratory Medicine; Research Institute for Diseases of Old Ages, Graduate School of Medicine, Juntendo University, Tokyo, JapanDepartment of Respiratory Medicine; Research Institute for Diseases of Old Ages, Graduate School of Medicine, Juntendo University, Tokyo, JapanDepartment of Respiratory Medicine; Research Institute for Diseases of Old Ages, Graduate School of Medicine, Juntendo University, Tokyo, JapanDepartment of Respiratory Medicine; Research Institute for Diseases of Old Ages, Graduate School of Medicine, Juntendo University, Tokyo, JapanDepartment of Respiratory Medicine; Research Institute for Diseases of Old Ages, Graduate School of Medicine, Juntendo University, Tokyo, JapanDepartment of Respiratory Medicine; Research Institute for Diseases of Old Ages, Graduate School of Medicine, Juntendo University, Tokyo, JapanDepartment of Respiratory Medicine; Research Institute for Diseases of Old Ages, Graduate School of Medicine, Juntendo University, Tokyo, JapanDepartment of Respiratory Medicine; Research Institute for Diseases of Old Ages, Graduate School of Medicine, Juntendo University, Tokyo, JapanDepartment of General Thoracic Surgery, Graduate School of Medicine, Juntendo University, Tokyo, JapanDepartment of Human Pathology, Graduate School of Medicine, Juntendo University, Tokyo, JapanDepartment of Orthopedic Surgery, Graduate School of Medicine, Juntendo University, Tokyo, JapanPharmaceutical Research and Technology Institute, School of Medicine, Kinki University, Osaka, JapanPharmaceutical Research and Technology Institute, School of Medicine, Kinki University, Osaka, JapanResearch Institute for Diseases of Old Ages, Graduate School of Medicine, Juntendo University, Tokyo; Atopic Research Center, Graduate School of Medicine, Juntendo University, Tokyo, JapanDepartment of Respiratory Medicine; Research Institute for Diseases of Old Ages, Graduate School of Medicine, Juntendo University, Tokyo, Japan 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. http://www.bjbms.org/ojs/index.php/bjbms/article/view/4227FBXW7quiescencecancer stem cellsgefitinib resistanceNSCLC |