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Kitatani, K, Sheldon, K, Rajagopalan, V, Anelli, V, Jenkins, RW, Sun, Y, Grabowski, GA, Obeid, LM and Hannun, YA (2009) Involvement of acid beta-glucosidase 1 in the salvage pathway of ceramide formation. J. Biol. Chem. 284:12972-8
Activation of protein kinase C (PKC) promotes the salvage pathway of ceramide formation, and acid sphingomyelinase has been implicated, in part, in providing substrate for this pathway (Zeidan, Y. H., and Hannun, Y. A. (2007) J. Biol. Chem. 282, 11549-11561). In the present study, we examined whether acid beta-glucosidase 1 (GBA1), which hydrolyzes glucosylceramide to form lysosomal ceramide, was involved in PKC-regulated formation of ceramide from recycled sphingosine. Glucosylceramide levels declined after treatment of MCF-7 cells with a potent PKC activator, phorbol 12-myristate 13-acetate (PMA). Silencing GBA1 by small interfering RNAs significantly attenuated acid glucocerebrosidase activity and decreased PMA-induced formation of ceramide by 50%. Silencing GBA1 blocked PMA-induced degradation of glucosylceramide and generation of sphingosine, the source for ceramide biosynthesis. Reciprocally, forced expression of GBA1 increased ceramide levels. These observations indicate that GBA1 activation can generate the source (sphingosine) for PMA-induced formation of ceramide through the salvage pathway. Next, the role of PKCdelta, a direct effector of PMA, in the formation of ceramide was determined. By attenuating expression of PKCdelta, cells failed to trigger PMA-induced alterations in levels of ceramide, sphingomyelin, and glucosylceramide. Thus, PKCdelta activation is suggested to stimulate the degradation of both sphingomyelin and glucosylceramide leading to the salvage pathway of ceramide formation. Collectively, GBA1 is identified as a novel source of regulated formation of ceramide, and PKCdelta is an upstream regulator of this pathway.
Blotting, Western; Breast Neoplasms/genetics; Breast Neoplasms/metabolism; Breast Neoplasms/pathology; Carcinogens/pharmacology; Cell Line, Tumor; Ceramides/biosynthesis; Chromatography, High Pressure Liquid; Female; Gene Silencing/physiology; Glucosylceramidase/physiology; Glucosylceramides/metabolism; Humans; Lysosomes/metabolism; Protein Kinase C/metabolism; RNA, Small Interfering/genetics; Sphingomyelins/metabolism; Sphingosine/metabolism; Tandem Mass Spectrometry; Tetradecanoylphorbol Acetate/pharmacology