Identification of the ZAK-MKK4-JNK-TGFβ Signaling Pathway as a Molecular Target for Novel Synthetic Iminoquinone Anticancer Compound BA-TPQ
2013
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:
- Correction
- Source
- Cite
- Save
- Machine Reading By IdeaReader
40
References
6
Citations
NaN
KQI