Open AccessPhytosphingosine induced mitochondria‐involved apoptosis
Author(s) -
Nagahara Yukitoshi,
Shinomiya Takahisa,
Kuroda Sachiko,
Kaneko Naoki,
Nishio Reiji,
Ikekita Masahiko
Publication year - 2005
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2005.00012.x
Subject(s) - apoptosis , sphingosine , sphingolipid , jurkat cells , microbiology and biotechnology , mitochondrion , cytochrome c , biology , protein kinase b , inhibitor of apoptosis domain , caspase , dna fragmentation , intrinsic apoptosis , programmed cell death , biochemistry , immunology , receptor , t cell , immune system
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 ΔΨ 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 p70 S6k . 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 ΔΨ m . These results indicate that phytosphingosine perturbs mitochondria both directly and indirectly to induce apoptosis. ( Cancer Sci 2005; 96: 83–92)