title: Inhibition of Glucosylceramide Synthase Sensitizes Head and Neck Cancer to Cisplatin.
abstract: 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.
authors.affiliation: Department of Otolaryngology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea. 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: 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: 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: Ji Won
authors.initials: JW
authors.lastname: Kim
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D015870:Gene Expression; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D023041:Xenograft Model Antitumor Assays
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase; D002945:Cisplatin