Identification of the ZAK-MKK4-JNK-TGF? signaling pathway as a molecular target for novel synthetic iminoquinone anticancer compound BA-TPQ.

ABSTRACT: Identification and validation of molecular targets are considered as key elements in new drug discovery and development. We have recently demonstrated that a novel synthetic iminoquinone analog, termed [7-(benzylamino)- 1,3,4,8-tetrahydropyrrolo [4,3, 2-de]quinolin-8(1H)-one] (BA-TPQ), has significant anti-breast cancer activity both in vitro and in vivo, but the underlying molecular mechanisms are not fully understood. Herein, we report the molecular studies for BA-TPQ's effects on JNK and its upstream and downstream signaling pathways. The compound up-regulates the JNK protein levels by increasing its phosphorylation and decreasing its polyubiquitination-mediated degradation. It activates ZAK at the MAPKKK level and MKK4 at the MAPKK level. It also up-regulates the TGF?2 mRNA level, which can be abolished by the JNK-specific inhibitor SP600125, but not TGF? pathway-specific inhibitor SD-208, indicating that both JNK and TGF? signaling pathways are activated by BA-TPQ and that the JNK pathway activation precedes TGF? activation. The pro-apoptotic and anti-growth effects of BA-TPQ are significantly blocked by both the JNK and TGF? pathway inhibitors. In addition, BA-TPQ activates the ZAK-MKK4-JNK pathway in MCF7 cells, but not normal MCF10A cells, demonstrating its cancer-specific activities. In conclusion, our results demonstrate that BA-TPQ activates the ZAK-MKK4-JNK-TGF? signaling cascade as a molecular target for its anticancer activity.

SUBMITTER: Chen D 

PROVIDER: S-EPMC6705132 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature