We have previously shown that the anti-tumorigenic indolylcytochalasin Chaetoglobosin K (ChK) concomitantly down-regulates Akt and JNK activation in ras-transformed cells. This dual inhibition was found not be regulated by Rac1, a Rho protein that is involved in both signaling pathways, or MKK4, an upstream kinase of JNK. The purpose of this study was to determine: 1) the effect of ChK on the activation of downstream mediators of the PI3K/Akt (including mdm2), and JNK (including the activator protein-1 (AP-1) proteins and stat3) signaling pathways; 2) whether the upstream mitogen-activated protein kinase kinase 7 (MKK7) is involved in ChK's effect on JNK. The AP-1 transcription factor complex, composed of proteins of the JUN, FOS, and ATF families, has become a promising therapeutic target due to the proposed role of AP-1 activation in tumorigenesis. In these studies, ras-transformed rat liver epithelial cells were grown to confluence and treated with either ChK (5μM or 10μM) or vehicle (DMSO) for 24 hours. Cell proteins were extracted and separated using SDS-PAGE. Western blot analysis was performed using phosphorylation site-specific antibodies to monitor changes in MKK7, c-JUN, ATF-2, mdm2, and stat3 protein activation levels. The results of these studies indicate that ChK treatment decreased c-JUN and ATF-2 phosphorylation, but had no effect on stat3 phosphorylation. Additionally, ChK treatment decreased mdm2 phosphorylation. ChK did not alter MKK7 activation levels and, taking into consideration its lack of effect on MKK4, suggest ChK does not inhibit JNK via its archetypical MAPK signaling pathway. These studies indicate ChK may serve as a small molecule inhibitor of the AP-1 pathway proteins, as well as the Akt/mdm2 pathway. This data further supports ChK's potential as a unique targeted tumor therapy. This project was funded by NIH grant 1R15CA135415

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1810. doi:1538-7445.AM2012-1810