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Investigational New Drugs

, Volume 31, Issue 3, pp 525–534 | Cite as

Dual modulation of JNK and Akt signaling pathways by chaetoglobosin K in human lung carcinoma and ras-transformed epithelial cells

  • Amna Ali
  • Tatyana S. Sidorova
  • Diane F. Matesic
PRECLINICAL STUDIES

Summary

Chaetoglobosin K (ChK) is a natural product that inhibits anchorage-dependent and anchorage-independent growth of ras-transformed cells, prevents tumor-promoter disruption of cell-cell communication, and reduces Akt activation in tumorigenic cells. This study demonstrates how ChK modulates the JNK pathway in ras-transformed and human lung carcinoma cells and investigates regulatory mechanisms controlling ChK’s effect on the Akt and JNK signaling pathways. Human lung carcinoma and ras-transformed epithelial cell lines treated with ChK or vehicle for varying times were assayed for cell growth or extracted for total proteins for western blot analysis using phosphorylation site-specific antibodies to monitor changes in activation of JNK, Akt, and other signaling enzymes. Results show that ChK inhibited both Akt and JNK phosphorylation at key activation sites in ras-transformed cells as well as human lung carcinoma cells. Downstream effectors of both kinases were accordingly affected. Direct upstream kinases of JNK were not affected by ChK. Wortmannin and LY294002, two PI3 kinase inhibitors, inhibited Akt but not JNK phosphorylation in ras-transformed cells. This report establishes the dual inhibitory effect of ChK on both the Akt and JNK signaling pathways in ras-transformed epithelial and human carcinoma cells. The unique effect of ChK on these two key pathways involved in carcinogenesis earmarks ChK for further studies to determine its molecular target(s) and in vivo anti-tumor potential.

Keywords

Chaetoglobosin K JNK Akt kinase Wortmannin LY294002 

Notes

Acknowledgments

This work was supported by the National Institute of Health, grant 1R15CA135415.

Conflict of interest

The authors declare that they have no conflict of interest.

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Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  • Amna Ali
    • 1
  • Tatyana S. Sidorova
    • 1
  • Diane F. Matesic
    • 1
  1. 1.Department of Pharmaceutical Sciences, College of Pharmacy and Health SciencesMercer UniversityAtlantaUSA

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