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BIM-Mediated AKT Phosphorylation Is a Key Modulator of Arsenic Trioxide-Induced Apoptosis in Cisplatin-Sensitive and -Resistant Ovarian Cancer Cells.
- Source :
-
PLoS ONE . 2011, Vol. 6 Issue 5, p1-14. 14p. - Publication Year :
- 2011
-
Abstract
- Background: Chemo-resistance to cisplatin-centered cancer therapy is a major obstacle to the effective treatment of human ovarian cancer. Previous reports indicated that arsenic trioxide (ATO) induces cell apoptosis in both drug-sensitive and - resistant ovarian cancer cells. Principal Findings: In this study, we determined the molecular mechanism of ATO-induced apoptosis in ovarian cancer cells. Our data demonstrated that ATO induced cell apoptosis by decreasing levels of phosphorylated AKT (p-AKT) and activating caspase-3 and caspase-9. Importantly, BIM played a critical role in ATO-induced apoptosis. The inhibition of BIM expression prevented AKT dephosphorylation and inhibited caspase-3 activation during cell apoptosis. However, surprisingly, gene silencing of AKT or FOXO3A had little effect on BIM expression and phosphorylation. Moreover, the activation of caspase-3 by ATO treatment improved AKT dephosphorylation, not only by cleaving the regulatory A subunit of protein phosphatase 2A (PP2A), but also by increasing its activation. Furthermore, our data indicated that the c-Jun Nterminal kinases (JNK) pathway is involved in the regulation of BIM expression. Conclusions: We demonstrated the roles of BIM in ATO-induced apoptosis and the molecular mechanisms of BIM expression regulated by ATO during ovarian cancer cell apoptosis. Our findings suggest that BIM plays an important role in regulating p-AKT by activating caspase-3 and that BIM mediates the level of AKT phosphorylation to determine the threshold for overcoming cisplatin resistance in ovarian cancer cells. [ABSTRACT FROM AUTHOR]
- Subjects :
- *PHOSPHORYLATION
*ARSENIC trioxide
*APOPTOSIS
*CISPLATIN
*CANCER cells
Subjects
Details
- Language :
- English
- ISSN :
- 19326203
- Volume :
- 6
- Issue :
- 5
- Database :
- Academic Search Index
- Journal :
- PLoS ONE
- Publication Type :
- Academic Journal
- Accession number :
- 73817249
- Full Text :
- https://doi.org/10.1371/journal.pone.0020586