Naringin sensitizes nasopharyngeal carcinoma cells to paclitaxel by inducing AKR1C3 expression

ObjectiveTo investigate whether naringin enhances the chemosensitivity of nasopharyngeal carcinoma-derived CNE2 cells to paclitaxel and identify potential molecular mediators.MethodsCNE2 cells were treated with naringin alone or in combination with paclitaxel, cisplatin, or 5-fluorouracil. Cell viability, proliferation, and migration were assessed using cell counting kit-8 and Transwell assays. Transcriptomic profiling followed by bioinformatic analysis of Gene Expression Omnibus datasets (GSE53819, GSE12452, and GSE102349) was performed to identify nasopharyngeal carcinoma prognosis-related genes. AKR1C3 overexpression was established via lentiviral transduction, and pharmacological inhibition was performed using ASP9521. mRNA and protein expression were validated using reverse transcription quantitative polymerase chain reaction and Western blot analysis.ResultsNaringin (160 μM) demonstrated a trend toward reducing the half-maximal inhibitory concentration of paclitaxel from 10.52 to 8.04 nM; however, it did not significantly alter sensitivity to cisplatin or 5-fluorouracil. Combined treatment with 2 nM paclitaxel and 160 μM naringin synergistically suppressed CNE2 proliferation and migration compared with that using either agent alone (p < 0.05). Bioinformatic analysis revealed that high AKR1C3 expression was correlated with improved survival in patients with nasopharyngeal carcinoma (p < 0.05), whereas high PAIP1, PRKDC, PTPRR, and COL12A1 expressions were correlated with poorer outcomes. Reverse transcription quantitative polymerase chain reaction confirmed that both naringin and paclitaxel upregulated AKR1C3 mRNA, with the combination producing the strongest effect. Gain-of-function studies demonstrated that AKR1C3 overexpression significantly enhanced paclitaxel sensitivity, with half-maximal inhibitory concentration values decreasing from 13.63 to 6.994 nM in CNE2 cells and from 8.534 to 4.668 nM in CNE1 cells. Furthermore, the specific AKR1C3 inhibitor, ASP9521, significantly attenuated the synergistic anti-proliferative and anti-migratory effects of paclitaxel + naringin in CNE2 cells, confirming that naringin enhances chemosensitivity to paclitaxel by upregulating AKR1C3 expression.ConclusionsNaringin sensitizes CNE2 cells to paclitaxel, potentially via AKR1C3 upregulation. This flavonoid may represent a low-toxicity adjunct to enhance the efficacy of paclitaxel in nasopharyngeal carcinoma.