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Penta-Acetyl Geniposide Induce Apoptosis in C6 Glioma Cells by Modulating the Activation of Neutral Sphingomyelinase-Induced p75 Nerve Growth Factor Receptor and Protein Kinase C Pathway

Department of Nursing, Hungkuang University, Sha Lu, Taichung, Taiwan (C.-H.P.); Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan (C.-N.H.); and Institute of Biochemistry and Biotechnology, Chung Shan Medical University, Taichung, Taiwan (S.-P.H., C.-J.W.)

In our previous studies, we demonstrated the apoptotic cascades protein kinase C (PKC) /c-Jun NH₂-terminal kinase (JNK)/Fas/caspases induced by penta-acetyl geniposide [(Ac)₅GP]. However, the upstream signals mediating PKC activation have not yet been clarified. Ceramide, mainly generated from the degradation of sphingomyelin, was hypothesized upstream above PKC in (Ac)₅GP-transduced apoptosis. Furthermore, nerve growth factor (NGF)/p75 is supposed to be involved because(Ac)₅GP-induced apoptosis was demonstrated previously in glioma cells. In the present study, (Ac)₅GP was shown to activate neutral sphingomyelinase (N-SMase) immediately, with its maximum at 15 min. The NGF and p75 enhanced by (Ac)₅GP was inhibited when added with GW4869, the N-SMase inhibitor, indicating NGF/p75 as the downstream signals of N-SMase/ceramide. To investigate whether N-SMase is involved in (Ac)₅GP-transduced apoptotic pathway, cells were treated with (Ac)₅GP added with or without GW4869. It showed that N-SMase inhibition blocked FasL expression and caspase 3 activation. Likewise, p75 antagonist peptide attenuated the FasL/caspase 3 expression. The PKC translocation induced by (Ac)₅GP was also eliminated by GW4869 and p75 antagonist peptide. To further confirm whether N-SMase activation plays an important role in (Ac)₅GP-induced apoptosis, cells were analyzed the apoptotic rate by 4', 6-diamidino-2-phenylindole (DAPI) staining. (Ac)₅GP-induced apoptosis was reduced 40 and 80% by 10 and 20 µM GW4869, respectively. It indicated that N-SMase activation is pivotal in (Ac)₅GP-mediated apoptosis. In conclusion, SMase and NGF/p75 are suggested to mediate upstream above PKC, thus transducing FasL/caspase cascades in (Ac)₅GP-induced apoptosis.

Address correspondence to: Dr. Chau-Jong Wang, Institute of Biochemistry and Biotechnology, College of Medicine, Chung Shan Medical University, 110, Section 1, Chien Kuo N. Road, Taichung 402, Taiwan. E-mail: wcj{at}csmu.edu.tw