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Sphingosine kinase 1 regulates the Akt/FOXO3a/Bim pathway and contributes to apoptosis resistance in glioma cells.
- Source :
-
PloS one [PLoS One] 2011; Vol. 6 (5), pp. e19946. Date of Electronic Publication: 2011 May 18. - Publication Year :
- 2011
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Abstract
- The aim of this study was to investigate the mechanism through which Sphingosine kinase-1 (SPHK1) exerts its anti-apoptosis activity in glioma cancer cells. We here report that dysregulation of SPHK1 alters the sensitivity of glioma to apoptosis both in vitro and in vivo. Further mechanistic study examined the expression of Bcl-2 family members, including Bcl-2, Mcl-1, Bax and Bim, in SPHK1-overexpressing glioma cells and revealed that only pro-apoptotic Bim was downregulated by SPHK1. Moreover, the transcriptional level of Bim was also altered by SPHK1 in glioma cells. We next confirmed the correlation between SPHK1 and Bim expression in primary glioma specimens. Importantly, increasing SPHK1 expression in glioma cells markedly elevated Akt activity and phosphorylated inactivation of FOXO3a, which led to downregulation of Bim. A pharmacological approach showed that these effects of SPHK1 were dependent on phosphatidylinositol 3-kinase (PI3K). Furthermore, effects of SPHK1 on Akt/FOXO3a/Bim pathway could be reversed by SPHK1 specific RNA interference or SPHK1 inhibitor. Collectively, our results indicate that regulation of the Akt/FOXO3a/Bim pathway may be a novel mechanism by which SPHK1 protects glioma cells from apoptosis, thereby involved in glioma tumorigenesis.
- Subjects :
- Animals
Apoptosis Regulatory Proteins genetics
Bcl-2-Like Protein 11
Blotting, Western
Brain Neoplasms genetics
Brain Neoplasms metabolism
Brain Neoplasms pathology
Forkhead Box Protein O3
Forkhead Transcription Factors antagonists & inhibitors
Forkhead Transcription Factors genetics
Glioma genetics
Glioma metabolism
Humans
Immunoenzyme Techniques
Luciferases metabolism
Membrane Proteins genetics
Mice
Mice, Nude
Phosphatidylinositol 3-Kinase
Phosphorylation
Phosphotransferases (Alcohol Group Acceptor) genetics
Proto-Oncogene Proteins genetics
Proto-Oncogene Proteins c-akt genetics
RNA, Messenger genetics
RNA, Small Interfering genetics
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction
Tumor Cells, Cultured
Apoptosis
Apoptosis Regulatory Proteins metabolism
Forkhead Transcription Factors metabolism
Glioma pathology
Membrane Proteins metabolism
Phosphotransferases (Alcohol Group Acceptor) metabolism
Proto-Oncogene Proteins metabolism
Proto-Oncogene Proteins c-akt metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 6
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 21625639
- Full Text :
- https://doi.org/10.1371/journal.pone.0019946