title: Glucosylceramide synthase and its functional interaction with RTN-1C regulate chemotherapeutic-induced apoptosis in neuroepithelioma cells.
abstract: Glucosylceramide synthase (GCS), the key enzyme in the biosynthesis of glycosphingolipids, has been implicated in many biological phenomena, including multidrug resistance. GCS inhibition, by both antisense and the specific inhibitor (D-threo)-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP), results in a drastic decrease of apoptosis induced by the p53-independent chemotherapeutic agent N-(4-hydroxyphenyl)retinamide in neuroepithelioma cells. By using the yeast two-hybrid system, we have identified a member of the reticulon (RTN) family (RTN-1C) as the major GCS-protein partner. Interestingly, RTN-1C not only interacts with GCS at Golgi/ER interface but also modulates its catalytic activity in situ. In fact, overexpression of RTN-1C sensitizes CHP-100 cells to fenretinide-induced apoptosis. These findings demonstrate a novel p53-independent pathway of apoptosis regulated by Golgi/endoplasmic reticulum protein interactions, which is relevant for cancer combined therapy.
authors.affiliation: Department of Biology, University of Rome Tor Vergata, 00133 Rome, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Di Sano
authors.forename: Barbara
authors.initials: B
authors.lastname: Fazi
authors.forename: Gennaro
authors.initials: G
authors.lastname: Citro
authors.forename: Penny E
authors.initials: PE
authors.lastname: Lovat
authors.forename: Gianni
authors.initials: G
authors.lastname: Cesareni
authors.forename: Mauro
authors.initials: M
authors.lastname: Piacentini
mesh_terms: D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D004721:Endoplasmic Reticulum / Q000201:enzymology / Q000378:metabolism; D017313:Fenretinide / Q000494:pharmacology; D005964:Glucosyltransferases / Q000235:genetics / Q000378:metabolism*; D006056:Golgi Apparatus / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D018241:Neuroectodermal Tumors, Primitive, Peripheral / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D017386:Sequence Homology, Amino Acid; D014162:Transfection
chemical_list: D000970:Antineoplastic Agents; D009419:Nerve Tissue Proteins; C081781:RTN1 protein, human; D017313:Fenretinide; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase