title: Ceramide synthase inhibitor fumonisin B1 inhibits apoptotic cell death in SCC17B human head and neck squamous carcinoma cells after Pc4 photosensitization.
abstract: The sphingolipid ceramide modulates stress-induced cell death and apoptosis. We have shown that ceramide generated via de novo sphingolipid biosynthesis is required to initiate apoptosis after photodynamic therapy (PDT). The objective of this study was to define the role of ceramide synthase (CERS) in PDT-induced cell death and apoptosis using fumonisin B1 (FB), a CERS inhibitor. We used the silicon phthalocyanine Pc4 for PDT, and SCC17B cells, as a clinically-relevant model of human head and neck squamous carcinoma. zVAD-fmk, a pan-caspase inhibitor, as well as FB, protected cells from death after PDT. In contrast, ABT199, an inhibitor of the anti-apoptotic protein Bcl2, enhanced cell killing after PDT. PDT-induced accumulation of ceramide in the endoplasmic reticulum and mitochondria was inhibited by FB. PDT-induced Bax translocation to the mitochondria and cytochrome c release were also inhibited by FB. These novel data suggest that PDT-induced cell death via apoptosis is CERS/ceramide-dependent.
authors.affiliation: Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA. dseparovic@wayne.edu.
authors.forename: Nithin B
authors.initials: NB
authors.lastname: Boppana
authors.forename: Mohamed
authors.initials: M
authors.lastname: Kodiha
authors.forename: Ursula
authors.initials: U
authors.lastname: Stochaj
authors.forename: Ho-sheng
authors.initials: HS
authors.lastname: Lin
authors.forename: Adriana
authors.initials: A
authors.lastname: Haimovitz-Friedman
authors.forename: Alicja
authors.initials: A
authors.lastname: Bielawska
authors.forename: Jacek
authors.initials: J
authors.lastname: Bielawski
authors.forename: George W
authors.initials: GW
authors.lastname: Divine
authors.forename: John A
authors.initials: JA
authors.lastname: Boyd
authors.forename: Mladen
authors.initials: M
authors.lastname: Korbelik
authors.forename: Duska
authors.initials: D
authors.lastname: Separovic
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002518:Ceramides / Q000032:analysis / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000737:chemistry / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D037341:Fumonisins / Q000494:pharmacology* / Q000627:therapeutic use; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007211:Indoles / Q000737:chemistry*; D013058:Mass Spectrometry; D008928:Mitochondria / Q000737:chemistry / Q000378:metabolism; D017646:Organosilicon Compounds / Q000737:chemistry*; D010088:Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010778:Photochemotherapy; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D002518:Ceramides; D004791:Enzyme Inhibitors; D037341:Fumonisins; D007211:Indoles; D017646:Organosilicon Compounds; D051028:bcl-2-Associated X Protein; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C082854:silicon phthalocyanine; C056933:fumonisin B1; D045304:Cytochromes c; D010088:Oxidoreductases; C108138:dihydroceramide desaturase