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Int. J. Mol. Sci. 2019, 20(2), 244; https://doi.org/10.3390/ijms20020244

YC-1 Prevents Tumor-Associated Tissue Factor Expression and Procoagulant Activity in Hypoxic Conditions by Inhibiting p38/NF-κB Signaling Pathway

1
Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
2
Research Center for Natural Product and Drug Development, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
3
Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan
*
Author to whom correspondence should be addressed.
Received: 13 December 2018 / Revised: 3 January 2019 / Accepted: 4 January 2019 / Published: 9 January 2019
(This article belongs to the Special Issue Drug Discovery, Development and Regulatory Affairs)
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Abstract

Tissue factor (TF) expressed in cancer cells has been linked to tumor-associated thrombosis, a major cause of mortality in malignancy. Hypoxia is a common feature of solid tumors and can upregulate TF. In this study, the effect of YC-1, a putative inhibitor of hypoxia-inducible factor-1α (HIF-1α), on hypoxia-induced TF expression was investigated in human lung cancer A549 cells. YC-1 selectively prevented hypoxia-induced TF expression and procoagulant activity without affecting the basal TF levels. Surprisingly, knockdown or pharmacological inhibition of HIF-1α failed to mimic YC-1′s effect on TF expression, suggesting other mechanisms are involved. NF-κB, a transcription factor for TF, and its upstream regulator p38, were activated by hypoxia exposure. Treatment of hypoxic A549 cells with YC-1 prevented the activation of both NF-κB and p38. Inhibition of p38 suppressed hypoxia-activated NF-κB, and inhibited TF expression and activity to similar levels as treatment with an NF-κB inhibitor. Furthermore, stimulation of p38 by anisomycin reversed the effects of YC-1. Taken together, our results suggest that YC-1 prevents hypoxia-induced TF in cancer cells by inhibiting the p38/NF-κB pathway, this is distinct from the conventional anticoagulants that systemically inhibit blood coagulation and may shed new light on approaches to treat tumor-associated thrombosis. View Full-Text
Keywords: tissue factor; hypoxia; cancer; procoagulant activity; MAP kinases tissue factor; hypoxia; cancer; procoagulant activity; MAP kinases
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Hsieh, K.-Y.; Wei, C.-K.; Wu, C.-C. YC-1 Prevents Tumor-Associated Tissue Factor Expression and Procoagulant Activity in Hypoxic Conditions by Inhibiting p38/NF-κB Signaling Pathway. Int. J. Mol. Sci. 2019, 20, 244.

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