title: Targeting acid ceramidase sensitises head and neck cancer to cisplatin.
abstract: BACKGROUND
  Acid 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.
  
  
  METHODS
  AC 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.
  
  
  RESULTS
  AC 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.
  
  
  CONCLUSIONS
  AC 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.
authors.affiliation: Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea. Electronic address: rohjl@amc.seoul.kr.
authors.forename: Jong-Lyel
authors.initials: JL
authors.lastname: Roh
authors.affiliation: Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Jin Young
authors.initials: JY
authors.lastname: Park
authors.affiliation: Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Eun Hye
authors.initials: EH
authors.lastname: Kim
authors.affiliation: Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors.forename: Hye Jin
authors.initials: HJ
authors.lastname: Jang
mesh_terms: D055573:Acid Ceramidase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002518:Ceramides / Q000378:metabolism; D002945:Cisplatin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D000067492:RNAi Therapeutics; D000077195:Squamous Cell Carcinoma of Head and Neck; D013997:Time Factors; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D002518:Ceramides; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; C526693:ASAH1 protein, human; D055573:Acid Ceramidase; D002945:Cisplatin
keywords: Acid ceramidase; Cell death; Ceramide; Cisplatin; Head and neck cancer