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

Academic Article

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 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. © 2013 Bentham Science Publishers.
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    Digital Object Identifier (doi)

    Author List

  • Chen D; Wang W; Qin JJ; Wang MH; Murugesan S; Nadkarni DH; Velu SE; Wang H; Zhang R
  • Start Page

  • 651
  • End Page

  • 660
  • Volume

  • 13
  • Issue

  • 6