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- Title
The pivotal role of c-Jun NH2-terminal kinase-mediated Beclin 1 expression during anticancer agents-induced autophagy in cancer cells.
- Authors
Li, D.-D.; Wang, L.-L.; Deng, R.; Tang, J.; Shen, Y.; Guo, J.-F.; Wang, Y.; Xia, L.-P.; Feng, G.-K.; Liu, Q. Q.; Huang, W.-L.; Zeng, Y.-X.; Zhu, X.-F.
- 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
- Subjects
AUTOPHAGY; CERAMIDES; CELL death; TRANSCRIPTION factors; CANCER cells; GENETICS
- Publication
Oncogene, 2009, Vol 28, Issue 6, p886
- ISSN
0950-9232
- Publication type
Article
- DOI
10.1038/onc.2008.441