Current Cancer Drug Targets

Ruiwen Zhang 
Texas Tech University Health Sciences Center
1300 Coulter Drive
Amarillo, TX 79106


Identification of the ZAK-MKK4-JNK-TGFβ Signaling Pathway as a Molecular Target for Novel Synthetic Iminoquinone Anticancer Compound BA-TPQ

Author(s): Deng Chen, Wei Wang, Jiang-Jiang Qin, Ming-Hai Wang, Srinivasan Murugesan, Dwayaja H. Nadkarni, Sadanandan E. Velu, Hui Wang, Ruiwen Zhang.


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 TGFβ2 mRNA level, which can be abolished by the JNK-specific inhibitor SP600125, but not TGFβ pathway-specific inhibitor SD-208, indicating that both JNK and TGFβ signaling pathways are activated by BA-TPQ and that the JNK pathway activation precedes TGFβ activation. The pro-apoptotic and anti-growth effects of BA-TPQ are significantly blocked by both the JNK and TGFβ 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-TGFβ signaling cascade as a molecular target for its anticancer activity.

Keywords: Apoptosis, ATF3, breast cancer, cancer molecular target, DDIT3, Jun, MAP kinase, synthetic marine drugs, TGFβ, ZAK-MKK4-JNK.

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Article Details

Year: 2013
Page: [651 - 660]
Pages: 10
DOI: 10.2174/15680096113139990040
Price: $58