title: 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.
authors.affiliation: Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, 1300 Coulter Drive, Amarillo, TX 79106, USA.
authors.forename: Deng
authors.initials: D
authors.lastname: Chen
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Jiang-Jiang
authors.initials: JJ
authors.lastname: Qin
authors.forename: Ming-Hai
authors.initials: MH
authors.lastname: Wang
authors.forename: Srinivasan
authors.initials: S
authors.lastname: Murugesan
authors.forename: Dwayaja H
authors.initials: DH
authors.lastname: Nadkarni
authors.forename: Sadanandan E
authors.initials: SE
authors.lastname: Velu
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.forename: Ruiwen
authors.initials: R
authors.lastname: Zhang
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D061986:MCF-7 Cells; D042361:Mammary Glands, Human / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D009363:Neoplasm Proteins / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011494:Protein Kinases / Q000737:chemistry / Q000378:metabolism; D055550:Protein Stability / Q000187:drug effects; D011758:Pyrroles / Q000009:adverse effects / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D015363:Quinolones / Q000009:adverse effects / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D053781:Transforming Growth Factor beta2 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: C553817:7-(benzylamino)-1,3,4,8-tetrahydropyrrolo(4,3,2-de)quinolin-8(1H)-one; D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D015363:Quinolones; C509041:TGFB2 protein, human; D053781:Transforming Growth Factor beta2; D011494:Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; C413047:MAP3K20 protein, human; D048670:MAP Kinase Kinase 4; C482559:MAP2K4 protein, human