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A Combined Systemic Strategy for Overcoming Cisplatin Resistance in Head and Neck Cancer: From Target Identification to Drug Discovery
- Source :
- Cancers, Vol 12, Iss 3482, p 3482 (2020), Cancers, Volume 12, Issue 11
- Publication Year :
- 2020
- Publisher :
- MDPI AG, 2020.
-
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&ndash<br />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.
- Subjects :
- 0301 basic medicine
Cancer Research
SPC25
lcsh:RC254-282
Article
Transcriptome
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
medicine
Gene silencing
Viability assay
celastrol
Cisplatin
mitotic division
biology
Chemistry
Cancer
medicine.disease
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
030104 developmental biology
Oncology
Cell culture
Celastrol
030220 oncology & carcinogenesis
Cancer research
biology.protein
head and neck cancer
cisplatin resistance
transcriptome
medicine.drug
RHEB
Subjects
Details
- Language :
- English
- ISSN :
- 20726694
- Volume :
- 12
- Issue :
- 3482
- Database :
- OpenAIRE
- Journal :
- Cancers
- Accession number :
- edsair.doi.dedup.....7fa2c9d21504db7749be947c7d60f88d