TY - JOUR
T1 - A combined systemic strategy for overcoming cisplatin resistance in head and neck cancer
T2 - From target identification to drug discovery
AU - Chen, Yin Ju
AU - You, Guo Rung
AU - Lai, Meng Yu
AU - Lu, Long Sheng
AU - Chen, Chang Yu
AU - Ting, Lai Lei
AU - Lee, Hsin Lun
AU - Kanno, Yuzuka
AU - Chiou, Jeng Fong
AU - Cheng, Ann Joy
N1 - Funding Information:
Funding: This research was supported by the Ministry of Science and Technology (MOST, MOST-105-2320-B-038-045), Taipei Medical University, grant number TMU-104-AE1-B26 and Chang Gung Memorial Hospital-Linko Medical Center (CMRPD1H0481-3).
Funding Information:
Acknowledgments: This work was financially supported by the “TMU Research Center of Cancer Translational Medicine” from The Featured ?reas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan.
Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/11
Y1 - 2020/11
N2 - Cisplatin is the first-line chemotherapy agent for head and neck cancer (HNC), but its therapeutic effects are hampered by its resistance. In this study, we employed systemic strategies to overcome cisplatin resistance (CR) in HNC. CR cells derived from isogenic HNC cell lines were generated. The CR related hub genes, functional mechanisms, and the sensitizing candidates were globally investigated by transcriptomic and bioinformatic analyses. Clinically, the prognostic significance was assessed by the Kaplan–Meier method. Cellular and molecular techniques, including cell viability assay, tumorsphere formation assay, RT-qPCR, and immunoblot, were used. Results showed that these CR cells possessed highly invasive and stem-like properties. A total of 647 molecules was identified, and the mitotic division exhibited a novel functional mechanism significantly related to CR. A panel of signature molecules, MSRB3, RHEB, ULBP1, and spindle pole body component 25 (SPC25), was found to correlate with poor prognosis in HNC patients. SPC25 was further shown as a prominent molecule, which markedly suppressed cancer stemness and attenuated CR after silencing. Celastrol, a nature extract compound, was demonstrated to effectively inhibit SPC25 expression and reverse CR phenotype. In conclusion, the development of SPC25 inhibitors, such as the application of celastrol, maybe a novel strategy to sensitize cisplatin for the treatment of refractory HNC.
AB - Cisplatin is the first-line chemotherapy agent for head and neck cancer (HNC), but its therapeutic effects are hampered by its resistance. In this study, we employed systemic strategies to overcome cisplatin resistance (CR) in HNC. CR cells derived from isogenic HNC cell lines were generated. The CR related hub genes, functional mechanisms, and the sensitizing candidates were globally investigated by transcriptomic and bioinformatic analyses. Clinically, the prognostic significance was assessed by the Kaplan–Meier method. Cellular and molecular techniques, including cell viability assay, tumorsphere formation assay, RT-qPCR, and immunoblot, were used. Results showed that these CR cells possessed highly invasive and stem-like properties. A total of 647 molecules was identified, and the mitotic division exhibited a novel functional mechanism significantly related to CR. A panel of signature molecules, MSRB3, RHEB, ULBP1, and spindle pole body component 25 (SPC25), was found to correlate with poor prognosis in HNC patients. SPC25 was further shown as a prominent molecule, which markedly suppressed cancer stemness and attenuated CR after silencing. Celastrol, a nature extract compound, was demonstrated to effectively inhibit SPC25 expression and reverse CR phenotype. In conclusion, the development of SPC25 inhibitors, such as the application of celastrol, maybe a novel strategy to sensitize cisplatin for the treatment of refractory HNC.
KW - Celastrol
KW - Cisplatin resistance
KW - Head and neck cancer
KW - Mitotic division
KW - SPC25
KW - Transcriptome
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U2 - 10.3390/cancers12113482
DO - 10.3390/cancers12113482
M3 - Article
AN - SCOPUS:85096448229
SN - 2072-6694
VL - 12
SP - 1
EP - 20
JO - Cancers
JF - Cancers
IS - 11
M1 - 3482
ER -