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First published on June 8, 2006; DOI: 10.1124/mol.106.022178

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Received for publication January 5, 2006.
Revised June 1, 2006.
Accepted for publication June 7, 2006.

Penta-Acetyl Geniposide Induce Apoptosis in C6 Glioma Cells by Modulating the Activation of Neutral Sphingomyelinase-Induced p75 NGF Receptor and PKC{delta} Pathway

Chiung-Huei Peng 1, Chien-Ning Huang 2, Shu-Ping Hsu 3, Chau-Jong Wang 3*

1 Department of Nursing, Hungkuang University, Sha Lu, Taichung, Taiwan 2 Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan 3 Institute of Biochemistry and Biotechnology, Chung Shan Medical University, Taichung, Taiwan

* Address correspondence to: E-mail: wcj{at}csmu.edu.tw

Abstract

In our previous studies, we demonstrated the apoptotic cascades PKC{delta}/ JNK/ Fas/ caspases induced by penta-acetyl geniposide ((Ac)5GP). However, the upstream signals mediating PKC{delta} activation have not yet been clarified. Ceramide, mainly generated from the degradation of sphingomyelin (SM), was hypothesized upstream above PKC{delta} in (Ac)5GP-transduced apoptosis. Furthermore, NGF/ p75 is supposed to be involved since (Ac)5GP-induced apoptosis was previously demonstrated in glioma cells. In the present study, (Ac)5GP showed to activate neutral sphingomyelinase (N-SMase) immediately with its maximum at 15 min. The NGF and p75 enhanced by (Ac)5GP was inhibited while 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. Similarly, p75 antagonist peptide attenuated the FasL/ caspase 3 expression. The PKC{delta} translocation induced by (Ac)5GP was also eliminated by GW4869 and p75 antagonist peptide. To further confirm if N-SMase activation plays an important role in (Ac)5GP-induced apoptosis, cells were analyzed the apoptotic rate by DAPI staining. (Ac)5GP-induced apoptosis was reduced 40 % and 80 % by 10 µM 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{delta}, thus transducing FasL/ caspase cascades in (Ac)5GP-induced apoptosis.


Key words: NGF/EGF, Protein Kinase C, Sphingolipids, MAP Kinase, Jun Kinase, Signaling network analyses, Apoptosis, Mechanisms of cell killing/apoptosis


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C. J. Clarke, J. M. Guthrie, and Y. A. Hannun
Regulation of Neutral Sphingomyelinase-2 (nSMase2) by Tumor Necrosis Factor-{alpha} Involves Protein Kinase C-{delta} in Lung Epithelial Cells
Mol. Pharmacol., October 1, 2008; 74(4): 1022 - 1032.
[Abstract] [Full Text] [PDF]


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