Glucosylceramide synthase and its functional interaction with RTN-1C regulate chemotherapeutic-induced apoptosis in neuroepithelioma cells.
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.
Di Sano
Federica
F
Department of Biology, University of Rome Tor Vergata, 00133 Rome, Italy.
Fazi
Barbara
B
Citro
Gennaro
G
Lovat
Penny E
PE
Cesareni
Gianni
G
Piacentini
Mauro
M
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
D000970:Antineoplastic Agents; D009419:Nerve Tissue Proteins; C081781:RTN1 protein, human; D017313:Fenretinide; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase