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Activation of tissue plasminogen activator gene transcription by Neovastat, a multifunctional antiangiogenic agent
Denis Gingras1, Carine Nyalendo, Geneviève Di Tomasso
1Laboratoire de médecine moléculaire, Hôpital Ste-Justine-UQAM, Centre de cancérologie Charles-Bruneau, Centre de Recherche de l'Hôpital Ste-Justine, 3175, Chemin Côte-Ste-Catherine, Montréal, Que., Canada H3T 1C5.
Abstract:
We recently reported that Neovastat, an antiangiogenic drug that is currently undergoing Phase III clinical trials for the treatment of non-small cell lung cancer, may inhibit angiogenesis through an increase in tPA activity. Here, we show that Neovastat also stimulates tPA gene transcription in endothelial cells, in a TNFalpha-like manner. RT-PCR analysis and gene reporter assays using the human tPA promoter indicated that upregulation of the tPA gene transcription by both Neovastat and TNFalpha was correlated with the phosphorylation of JNK1/2 and of IkappaB and that SP600125 and BAY11-7082, inhibitors of JNK and IkappaK, respectively, inhibit the increase of tPA gene transcription induced by Neovastat and TNFalpha. These results suggest that Neovastat induces tPA gene transcription through activation of the JNK and NFkappaB signaling pathways, leading to an increase of tPA secretion by endothelial cells. This may lead to the localized destruction of the fibrin provisional matrix that is necessary for neovessel formation and thus contribute to the reported antiangiogenic properties of this compound.
Insights
Neovastat, an antiangiogenic drug, stimulates tissue plasminogen activator (tPA) gene transcription in endothelial cells. This activation of signaling pathways contributes to Neovastat's antiangiogenic effects in cancer treatment.
Area of Science:
- Molecular Biology
- Pharmacology
- Oncology
Background:
- Neovastat is an antiangiogenic drug in Phase III trials for non-small cell lung cancer.
- Previous findings suggested Neovastat inhibits angiogenesis via increased tissue plasminogen activator (tPA) activity.
Purpose of the Study:
- To investigate the mechanism by which Neovastat influences tPA gene transcription.
- To elucidate the role of specific signaling pathways in Neovastat-induced tPA expression.
Main Methods:
- Reverse transcription-polymerase chain reaction (RT-PCR) analysis.
- Gene reporter assays utilizing the human tPA promoter.
- Inhibition studies using JNK (SP600125) and IKK (BAY11-7082) pathway inhibitors.
Main Results:
- Neovastat stimulates tPA gene transcription in endothelial cells, mimicking TNFalpha.
- Upregulation of tPA transcription by Neovastat and TNFalpha correlates with JNK1/2 and IkappaB phosphorylation.
- Inhibitors of JNK and IKK pathways block Neovastat- and TNFalpha-induced tPA gene transcription.
Conclusions:
- Neovastat induces tPA gene transcription via activation of the JNK and NF-kappaB signaling pathways.
- This mechanism leads to increased tPA secretion, potentially degrading the fibrin matrix essential for neovascularization.
- The findings support Neovastat's antiangiogenic properties by elucidating its molecular mechanism involving tPA.
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