A combined systemic strategy for overcoming cisplatin resistance in head and neck cancer: From target identification to drug discovery

Yin Ju Chen, Guo Rung You, Meng Yu Lai, Long Sheng Lu, Chang Yu Chen, Lai Lei Ting, Hsin Lun Lee, Yuzuka Kanno, Jeng Fong Chiou, Ann Joy Cheng

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Article number3482
Pages (from-to)1-20
Number of pages20
JournalCancers
Volume12
Issue number11
DOIs
Publication statusPublished - Nov 2020

Keywords

  • Celastrol
  • Cisplatin resistance
  • Head and neck cancer
  • Mitotic division
  • SPC25
  • Transcriptome

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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