Targeting acid ceramidase sensitises head and neck cancer to cisplatin

Abstract

BackgroundAcid ceramidase (AC), a key enzyme in ceramide metabolism, plays a role in cancer progression and resistance to therapy. However, the role of AC in head and neck cancer (HNC) has not been addressed. Here, we investigate the effect of AC inhibition on the response to cisplatin-based chemotherapy for HNC. MethodsAC protein and messenger RNA (mRNA) expression were examined in primary tumours and paired normal tissues, and in HNC cell lines. The effects of genetic and pharmacological AC inhibition using small hairpin RNA (shRNA) and N-oleoyl-ethanolamine (NOE), alone and in combination with cisplatin, were assessed in human HNC cells by measuring cell viability, cell cycle progression, apoptosis, mRNA, and protein expression, and in preclinical tumour xenograft mouse models. FindingsAC overexpression was observed in four of six primary tumour tissues and six of nine HNC cell lines. Cisplatin sensitivity was significantly decreased by AC overexpression and significantly increased by AC downregulation in HNC cells (P<0.01). NOE or AC shRNA-mediated AC inhibition enhanced cisplatin-induced HNC cell death by increasing ceramide production and activating pro-apoptotic proteins, and these effects were abrogated by PUMA small interfering RNA transfection. AC inhibition promoted cisplatin-induced apoptosis of HNC cells in vitro and in vivo. InterpretationsAC overexpression is associated with cisplatin sensitivity, suggesting its potential role as a chemotherapeutic target for HNC. Genetic or pharmacological AC inhibition promotes cisplatin cytotoxicity in HNC cells.