Phytosphingosine induced mitochondria-involved apoptosis.

Abstract

Sphingolipids are putative intracellular signal mediators in cell differentiation, growth inhibition, and apoptosis. Sphingosine, sphinganine, and phytosphingosine are structural analogs of sphingolipids and are classified as long-chain sphingoid bases. Sphingosine and sphinganine are known to play important roles in apoptosis. In the present study, we examined the phytosphingosine-induced apoptosis mechanism, focusing on mitochondria in human T-cell lymphoma Jurkat cells. Phytosphingosine significantly induced chromatin DNA fragmentation, which is a hallmark of apoptosis. Enzymatic activity measurements of caspases revealed that caspase-3 and caspase-9 are activated in phytosphingosine-induced apoptosis, but there is little activation of caspase-8 suggesting that phytosphingosine influences mitochondrial functions. In agreement with this hypothesis, a decrease in DeltaPsi(m) and the release of cytochrome c to the cytosol were observed upon phytosphingosine treatment. Furthermore, overexpression of mitochondria-localized anti-apoptotic protein Bcl-2 prevented phytosphingosine apoptotic stimuli. Western blot assays revealed that phytosphingosine decreases phosphorylated Akt and p70S6k. Dephosphorylation of Akt was partially inhibited by protein phosphatase inhibitor OA and OA attenuated phytosphingosine-induced apoptosis. Moreover, using a cell-free system, phytosphingosine directly reduced DeltaPsi(m). These results indicate that phytosphingosine perturbs mitochondria both directly and indirectly to induce apoptosis.

• Authors: Yukitoshi Nagahara, Takahisa Shinomiya, Sachiko Kuroda, Naoki Kaneko, Reiji Nishio, Masahiko Ikekita
• Journal: Cancer science (Cancer Sci) Vol. 96 Issue 2 Pg. 83-92 (Feb 2005) ISSN: 1347-9032 [Print] England
• PMID: 15723652 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Proto-Oncogene Proteins c-bcl-2
• Cytochromes c
• Caspases
• phytosphingosine
• Sphingosine

Topics

• Apoptosis (drug effects)
• Caspases (metabolism)
• Cytochromes c (metabolism)
• DNA Fragmentation
• Dose-Response Relationship, Drug
• Humans
• Membrane Potentials (drug effects)
• Mitochondria (metabolism)
• Phosphorylation
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Sphingosine (analogs & derivatives, pharmacology)