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The pivotal role of c-Jun NH2-terminal kinase-mediated Beclin 1 expression during anticancer agents-induced autophagy in cancer cells.
- Source :
- Oncogene; 2/12/2009, Vol. 28 Issue 6, p886-898, 13p, 1 Black and White Photograph, 6 Graphs
- Publication Year :
- 2009
-
Abstract
- The c-Jun NH2-terminal kinase (JNK) pathway represents one subgroup of MAP kinases that are activated primarily by cytokines and exposure to environmental stress. Autophagy is a protein-degradation system characterized by the formation of double-membrane vacuoles termed autophagosomes. Autophagy-related gene beclin 1 plays a key role in autophagosome formation. However, the relationships between activation of JNK pathway, autophagy induction and Beclin 1 expression remain elusive. In this study, we used human cancer cell lines CNE2 and Hep3B to investigate the role of JNK-mediated Beclin 1 expression in ceramide-induced autophagic cell death. Ceramide-treated cells exhibited the characteristics of autophagy (that is, acidic vesicular organelle formation and the LC3-II generation). JNK was activated in these two cell lines exposed to ceramide and the phosphorylation of c-Jun also increased. In the meantime, we found that ceramide upregulated Beclin 1 expression in cancer cells. The upregulation of Beclin 1 expression could be blocked by SP600125 (a specific inhibitor of JNK) or a small interfering RNA (siRNA) directed against JNK1/2 or c-Jun. Chromatin immunoprecipitation and luciferase reporter analysis revealed that c-Jun was involved in the regulation of beclin 1 transcription in response to ceramide treatment. In addition, inhibition of JNK activity by SP600125 could inhibit autophagy induction by ceramide. Furthermore, Beclin 1 knockdown by siRNA also inhibited ceramide-mediated autophagic cell death. JNK-mediated Beclin 1 expression was also observed in topotecan-induced autophagy. These data suggest that activation of JNK pathway can mediate Beclin 1 expression, which plays a key role in autophagic cell death in cancer cells.Oncogene (2009) 28, 886–898; doi:10.1038/onc.2008.441; published online 8 December 2008 [ABSTRACT FROM AUTHOR]
- Subjects :
- AUTOPHAGY
CERAMIDES
CELL death
TRANSCRIPTION factors
CANCER cells
GENETICS
Subjects
Details
- Language :
- English
- ISSN :
- 09509232
- Volume :
- 28
- Issue :
- 6
- Database :
- Complementary Index
- Journal :
- Oncogene
- Publication Type :
- Academic Journal
- Accession number :
- 36472800
- Full Text :
- https://doi.org/10.1038/onc.2008.441