HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Identification of the ZAK-MKK4-JNK-TGFβ 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 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.
AuthorsDeng Chen, Wei Wang, Jiang-Jiang Qin, Ming-Hai Wang, Srinivasan Murugesan, Dwayaja H Nadkarni, Sadanandan E Velu, Hui Wang, Ruiwen Zhang
JournalCurrent cancer drug targets (Curr Cancer Drug Targets) Vol. 13 Issue 6 Pg. 651-60 (Jul 2013) ISSN: 1873-5576 [Electronic] Netherlands
PMID23607596 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • 7-(benzylamino)-1,3,4,8-tetrahydropyrrolo(4,3,2-de)quinolin-8(1H)-one
  • Antineoplastic Agents
  • Neoplasm Proteins
  • Protein Kinase Inhibitors
  • Pyrroles
  • Quinolones
  • TGFB2 protein, human
  • Transforming Growth Factor beta2
  • Protein Kinases
  • JNK Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinases
  • MAP3K20 protein, human
  • MAP Kinase Kinase 4
  • MAP2K4 protein, human
Topics
  • Antineoplastic Agents (adverse effects, antagonists & inhibitors, pharmacology)
  • Apoptosis (drug effects)
  • Breast Neoplasms (drug therapy, enzymology, metabolism)
  • Cell Line
  • Cell Proliferation (drug effects)
  • Female
  • Humans
  • JNK Mitogen-Activated Protein Kinases (antagonists & inhibitors, chemistry, metabolism)
  • MAP Kinase Kinase 4 (antagonists & inhibitors, metabolism)
  • MAP Kinase Kinase Kinases
  • MAP Kinase Signaling System (drug effects)
  • MCF-7 Cells
  • Mammary Glands, Human (drug effects, enzymology, metabolism)
  • Neoplasm Proteins (agonists, antagonists & inhibitors, genetics, metabolism)
  • Neoplasms (drug therapy, metabolism)
  • Phosphorylation (drug effects)
  • Protein Kinase Inhibitors (pharmacology)
  • Protein Kinases (chemistry, metabolism)
  • Protein Stability (drug effects)
  • Pyrroles (adverse effects, antagonists & inhibitors, pharmacology)
  • Quinolones (adverse effects, antagonists & inhibitors, pharmacology)
  • Transforming Growth Factor beta2 (agonists, antagonists & inhibitors, genetics, metabolism)
  • Ubiquitination (drug effects)
  • Up-Regulation (drug effects)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: