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. The effect of genetic or pharmacologic GCS inhibition (using GCS
siRNA/
shRNA or d,l-threo-
PPMP, respectively) on
cisplatin sensitivity was assessed in several human HNC cells and acquired
cisplatin-resistant HNC cells by measuring cell viability, cell cycle, death,
mRNA and
protein expression,
ceramide production, and in preclinical
tumor xenograft mouse models. GCS and P-gp expression were significantly associated 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 pharmacologic inhibition of GCS induced accumulation of increased
ceramide levels. GCS inhibition increased
cisplatin-induced cell death in HNC cells via P-gp downregulation and proapoptotic
protein activation, which were abrogated by siPUMA transfection. Genetic and pharmacologic GCS inhibition sensitized resistant HNC cells to
cisplatin in vitro and in vivo. GCS and P-gp overexpression is associated with acquired
cisplatin resistance, suggesting a role for these molecules as therapeutic targets for HNC. Genetic or pharmacologic GCS blockade may have therapeutic benefit in
cisplatin-resistant HNC.