Chaetoglobosin K (ChK) is a natural indolylcytochalasin that has been reported to inhibit the proliferation of human lung and ovarian carcinoma cells in vitro. We have previously shown that ChK concomitantly down-regulates Akt and JNK activation, and have recently determined that the inhibition of Akt by ChK is not via direct inhibition of the upstream enzyme PI3 kinase. The reduction in Akt activation after ChK treatment is also not related to changes in phosphorylation of the upstream modulators PDK1 or PTEN. The mammalian target of rapamycin (mTOR) is a kinase that regulates cell growth and protein synthesis and can be both upstream (mTORC2) and downstream (mTORC1) of Akt. The purpose of this study was to determine whether ChK: 1) decreases the activation of upstream mTORC2, as this may lead to a decrease in Akt phosphorylation; 2) alters the phosphorylation of downstream mTORC1 mediators 4E-BP1 and p70 S6 kinase. In these studies, ras-transformed rat liver epithelial cells were treated with either a non-cytotoxic dose of ChK or vehicle. Western blot analysis was performed using phosphorylation site-specific antibodies to monitor changes in 4E-BP1, p70 S6 kinase, and mTOR protein activation levels. The results of this study indicate that ChK treatment did not decrease mTORC2 activation levels and suggest that ChK decreases Akt phosphorylation through an alternate mechanism. ChK treatment decreased the phosphorylation of 4E-BP1 and p70 S6 kinase, confirming that ChK modulates downstream Akt/mTOR pathway effectors. Further investigations are warranted to determine the exact mechanism by which ChK down-regulates Akt, as well as JNK, activation in tumorigenic cells.

This project was funded by NIH grant 1R15CA135415

Citation Format: Amna Ali, Diane F. Matesic. Chaetoglobosin K, a dual Akt and JNK inhibitor, modulates Akt phosphorylation in an mTORC2 independent manner. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4523. doi:10.1158/1538-7445.AM2014-4523

©2014 American Association for Cancer Research.
2014