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Glucosylceramide Synthase and Its Functional Interaction with RTN-1C Regulate Chemotherapeutic-induced Apoptosis in Neuroepithelioma Cells¹

Department of Biology, University of Rome "Tor Vergata," 00133 Rome, Italy [F. D., B. F., G. Ce., M. P.]; Istituto Regina Elena, 00156 Rome, Italy [G. Ci.]; Northern Institute of Cancer Research and School of Clinical Medical Sciences, University of Newcastle upon Tyne, Newcastle upon Tyne NE2 4HH, United Kingdom [P. E. L.]; and Cell Biology and E.M. Unit, INMI, IRCCS "Lazzaro Spallanzani," Rome, Italy [M. P.]

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.

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