목적: Glucosylceramide synthase (GCS) overexpression is associated with multidrug resistance in several human cancers. GCS blockade, which overcomes multidrug resistance by downregulating P-glycoprotein (P-gp), has not been tested in head and neck cancer (HNC). This study investigates whether GCS is targetable in HNC by assessing whether GCS inhibition sensitizes HNC to cisplatin. 방법:The association between GCS or P-gp overexpression and clinical outcomes was examined in 186 HNC human clinical specimens. The effect of genetic or pharmacological GCS inhibition (using GCS siRNA/shRNA or D,L-threo-PPMP, respectively) on cisplatin sensitivity was assessed in human HNC cells by measuring cell viability, cell cycle, death, mRNA and protein expression, and in preclinical tumor xenograft mouse models. 결과:GCS overexpression was observed in 128 (68.8%) patients and P-gp overexpression in 43 (23.1%) patients. GCS and P-gp expression were significantly associated with poor disease-free survival (P < 0.01) and with cisplatin resistance in several HNC cell lines (P = 0.007). Both were significantly increased in HN9-cisR cells, which display acquired cisplatin resistance (P < 0.001). Genetic or pharmacological inhibition of GCS increased cisplatin-induced cell death in HNC cells via P-gp downregulation and pro-apoptotic protein activation, which were abrogated by siPUMA transfection. Genetic and pharmacological GCS inhibition sensitized resistant HNC cells to cisplatin in vitro and in vivo. 결론:GCS and P-gp overexpression is associated with poor prognosis, suggesting a role for these molecules as novel biomarkers and therapeutic targets for HNC. Genetic or pharmacological GCS blockade may have therapeutic benefit in cisplatin-resistant HNC.