Abstract
Simple SummaryThe efficiency of cisplatin is limited by drug resistance in head–neck cancer (HNC) patients. In this study, we established a cisplatin resistance (CR) cell model, generated CR related transcriptome profiling, and combined application of bioinformatics methodology to discover a possible way to overcome CR. Analysis of the functional pathway revealed that mitotic division is a novel mechanism significantly contributing to CR. Spindle pole body component 25 (SPC25), a kinetochore protein, was overexpressed in CR cells and significantly correlated with worse HNC patient survival. The silencing of SPC25 increased cisplatin sensitivity and reduced cancer stemness property. Integration of CR transcriptome profiling and drug database discovered a natural extract compound, celastrol, possessing a potent cytotoxic effect in CR cells to reverse CR. Thus, we combined systemic strategies to demonstrated that a novel biological process (mitotic cell division), a hub gene (SPC25), and a natural compound (celastrol) as novel strategies for the treatment of refractory HNC.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.
Highlights
The incidence of head and neck cancer (HNC) has continued to rise to approximately11% in 2018 [1], with over 1.9 million individuals diagnosed with HNC at that time
The cytotoxic effects of celastrol were validated in three intrinsic cisplatin resistance (CR) cell lines (CGHNC8, CGHNC9, NPC076) and effective to intrinsic cisplatin-sensitive cells as well
Our results suggest that celastrol may be a potent compound to overcome cisplatin resistance in HNC cells
Summary
11% in 2018 [1], with over 1.9 million individuals diagnosed with HNC at that time. Cisplatin is considered the standard therapy for HNC patients. Some patients had good treatment outcomes after they were administered a high-dose of cisplatin (100 mg per square meter of body surface area intravenously every 21 days for three cycles); recurrence still develops in more than 65% of the HNC patients [5], which suggests the necessity for understanding the mechanisms of cisplatin resistance to explore a new approach to improve therapeutic outcomes. Three common mechanisms of cisplatin resistance (CR) in HNC cells have been reported [6,7,8,9]. The first is the nucleotide excision repair, wherein HNC cells survive cisplatin-induced
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