The pivotal role of c-Jun NH2-terminal kinase-mediated Beclin 1 expression during anticancer agents-induced autophagy in cancer cells.

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.

• Authors: D-D Li, L-L Wang, R Deng, J Tang, Y Shen, J-F Guo, Y Wang, L-P Xia, G-K Feng, Q Q Liu, W-L Huang, Y-X Zeng, X-F Zhu
• Journal: Oncogene (Oncogene) Vol. 28 Issue 6 Pg. 886-98 (Feb 12 2009) ISSN: 1476-5594 [Electronic] England
• PMID: 19060920 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anthracenes
• Antineoplastic Agents
• Apoptosis Regulatory Proteins
• BECN1 protein, human
• Beclin-1
• Ceramides
• Enzyme Inhibitors
• Membrane Proteins
• RNA, Small Interfering
• pyrazolanthrone
• JNK Mitogen-Activated Protein Kinases
• MAP Kinase Kinase 4
• Caspase 3

Topics

• Anthracenes (pharmacology)
• Antineoplastic Agents (pharmacology)
• Apoptosis Regulatory Proteins (metabolism)
• Autophagy
• Beclin-1
• Caspase 3 (metabolism)
• Cell Line, Tumor
• Ceramides (metabolism)
• Enzyme Inhibitors (pharmacology)
• Gene Expression Regulation, Neoplastic
• Humans
• JNK Mitogen-Activated Protein Kinases (metabolism)
• MAP Kinase Kinase 4 (metabolism)
• Membrane Proteins (metabolism)
• Phagosomes (metabolism)
• Phosphorylation
• RNA, Small Interfering (metabolism)