| Budget Amount *help |
¥12,400,000 (Direct Cost: ¥12,400,000)
Fiscal Year 2001: ¥5,100,000 (Direct Cost: ¥5,100,000)
Fiscal Year 2000: ¥7,300,000 (Direct Cost: ¥7,300,000)
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| Research Abstract |
Abundant studies have provided substantial evidence to indicate that sphingolipid metabolism, ceramide, plays a key role in induction of apoptosis. The anti-cancer drug, camptothecine (CPT) induced genotoxic apoptosis in human prostate cancer LNCaP cells. During the apoptosis intracellular ceramide level was elevated time-dependently after CPT-treatment. No changes were observed in activities of both neutral and acid SMases. The pretreatment with the inhibitor of ceramide synthesis, fumonisin Bi, almost completely abrogated marked ceramide accumulation. These results suggest evidence that ceramide is produced via de novo pathway but not via sphingomyelin hydrolysis pathway. Furthermore, it was to be noted that the same treatment with fumonisin Bi did not affect DNA fragmentation as assessed by ladder formation, thereby leading us to propose that ceramide accumulation may be independent of apoptosis in this system. Sphingosine 1-phosphate (SiP) is known to act as antiapoptosis. SiP stimulation of EDG3-overexpressing CHO cells induced activation of survival signaling enzymes, PLD, PT 3-kinase, and Akt. SiP-induced activation of PT 3-kinase and Akt was abrogated by 1-butanol, which inhibited SiP-induced accumulation of phosphatidic acid (PA) by PLD, suggesting that PLD participates in the activation of PT 3-kinase and Akt. Furthermore, it has been demonstrated that TNF-α induced sphingosine kinase (SPHK) activation in human hepatocytes, and dimethyisphingosine, a SPHK inhibitor, inhibited PI3K/Akt pathway and potentiated TNF-α-mediated hepatocyte apoptosis. These results suggest that SPHK and SiP play a role in cell survival through activation of PI3K/Akt signaling pathway.
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