Fisetin, a dietary flavonoid, increases the sensitivity of chemoresistant head and neck carcinoma cells to cisplatin possibly through HSP90AA1/IL-17 pathway

Cisplatin (DDP) resistance is a bottleneck in the treatment of head and neck cancer (HNC), leading to poor prognosis. Fisetin, a dietary flavonoid, has low toxicity and high antitumor activity with unclear mechanisms. We intended to predict the targets of fisetin for reversing DDP-resistance and further verify their expressions and roles. A network pharmacology approach was applied to explore the target genes. The hub genes were screened out and subjected to molecular docking and experimental verification (in vivo and in vitro). Thirty-two genes common to fisetin and DDP-resistance were screened, including three hub genes, namely HSP90AA1, PPIA, and PTPRS. Molecular docking suggested that fisetin and the candidate proteins could bind tightly. HSP90AA1 was identified as the key gene. Administration of fisetin increased the sensitivity of chemoresistant cells (Cal27/DDP and FaDu/DDP) to DDP, accompanied by the downregulation of HSP90AA1 and IL-17. HSP90AA1 silencing increases the sensitivity of DDP-resistant cells to DDP, which was mediated by IL-17. In summary, fisetin might inhibit the chemoresistance of HNC cells to DDP by targeting the HSP90AA1/IL-17 pathway. Several hub genes might be the targets of fisetin for reversing DDP-resistance in HNC cells and might also serve as prognostic factors and therapeutic targets for HNC.

Automated summary

This study found that fisetin, a dietary flavonoid, can reverse chemoresistance and increase the sensitivity of head and neck cancer cells to cisplatin (DDP). Through network pharmacology analysis, 32 genes were identified as common targets of fisetin and DDP-resistance, including HSP90AA1, PPIA, and PTPRS. Molecular docking experiments confirmed the strong binding between fisetin and these candidate proteins. Fisetin increased DDP sensitivity by downregulating HSP90AA1 and IL-17. This study highlights the potential of fisetin as a therapeutic agent for reversing DDP-resistance in head and neck cancer cells.