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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / adverse effects
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Antineoplastic Agents / antagonists & inhibitors
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Antineoplastic Agents / pharmacology*
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Apoptosis / drug effects
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Breast Neoplasms / drug therapy*
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Breast Neoplasms / enzymology
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Breast Neoplasms / metabolism
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Cell Line
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Cell Proliferation / drug effects
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Female
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Humans
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JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors
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JNK Mitogen-Activated Protein Kinases / chemistry
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JNK Mitogen-Activated Protein Kinases / metabolism
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MAP Kinase Kinase 4 / antagonists & inhibitors
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MAP Kinase Kinase 4 / metabolism
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MAP Kinase Kinase Kinases
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MAP Kinase Signaling System / drug effects*
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MCF-7 Cells
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Mammary Glands, Human / drug effects
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Mammary Glands, Human / enzymology
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Mammary Glands, Human / metabolism
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Neoplasm Proteins / agonists
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Neoplasm Proteins / antagonists & inhibitors*
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism
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Neoplasms / drug therapy*
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Neoplasms / metabolism
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Phosphorylation / drug effects
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Protein Kinase Inhibitors / pharmacology
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Protein Kinases / chemistry
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Protein Kinases / metabolism
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Protein Stability / drug effects
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Pyrroles / adverse effects
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Pyrroles / antagonists & inhibitors
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Pyrroles / pharmacology*
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Quinolones / adverse effects
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Quinolones / antagonists & inhibitors
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Quinolones / pharmacology*
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Transforming Growth Factor beta2 / agonists
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Transforming Growth Factor beta2 / antagonists & inhibitors
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Transforming Growth Factor beta2 / genetics
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Transforming Growth Factor beta2 / metabolism
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Ubiquitination / drug effects
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Up-Regulation / drug effects*
Substances
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7-(benzylamino)-1,3,4,8-tetrahydropyrrolo(4,3,2-de)quinolin-8(1H)-one
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Antineoplastic Agents
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Neoplasm Proteins
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Protein Kinase Inhibitors
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Pyrroles
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Quinolones
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TGFB2 protein, human
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Transforming Growth Factor beta2
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Protein Kinases
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JNK Mitogen-Activated Protein Kinases
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MAP Kinase Kinase Kinases
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MAP3K20 protein, human
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MAP Kinase Kinase 4
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MAP2K4 protein, human