P14ARF Suppresses Tumor-Induced Thrombosis by Regulating the Tissue Factor Pathway

• Type of Material: Article
• Authors: Abdessamad Zerrouqi, Emory University; Beata Pyrzynska, Emory University; Daniel Brat, Emory University; Erwin Van Meir, Emory University
• Language: English
• Date: 2014-03-01
• Publisher: American Association for Cancer Research
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2013 American Association for Cancer Research.
• Final Published Version (URL): http://dx.doi.org/10.1158/0008-5472.CAN-13-1951
• Title of Journal or Parent Work: Cancer Research
• ISSN: 0008-5472
• Volume: 74
• Issue: 5
• Start Page: 1371
• End Page: 1378
• Grant/Funding Information: We thank Dr. Walter Kisiel, (Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland) for providing the anti-TFPI2 antibody, Dr. Christina Kast (Biotechnology Research Institute, Montreal, Canada) for providing the TFPI2-luciferase reporter plasmids and Dr. Russ Pieper (UCSF, San Francisco, USA) for providing the transformed human astrocytes.; This work was supported by grants from the NIH CA86335, CA116804 (to EGVM) and CA149107 (to DJB), the Southeastern Brain Tumor Foundation (to A.Z and EGVM), and P30 CA138292 to the Winship Cancer Institute.
• Keywords: Oncology; IN-VIVO; FACTOR EXPRESSION; Science & Technology; ENDOTHELIAL GROWTH-FACTOR; INHIBITOR-2; Life Sciences & Biomedicine; ANGIOGENESIS; FACTOR RECEPTOR; EPIGENETIC INACTIVATION; HUMAN GLIOBLASTOMA; HYPOXIA; TFPI-2
• Research Categories: Health Sciences, Oncology

Abstract

How necrotic areas develop in tumors is incompletely understood but can impact progression. Recent findings suggest that the formation of vascular microthrombi contributes to tumor necrosis, prompting investigation of coagulation cascades. Here, we report that loss of tumor suppressor P14ARF can contribute to activating the clotting cascade in glioblastoma. P14ARF transcriptionally upregulated TFPI2, a Kunitz-type serine protease in the tissue factor pathway that inhibits the initiation of thrombosis reactions. P14ARF activation in tumor cells delayed their ability to activate plasma clotting. Mechanistically, P14ARF activated the TFPI2 promoter in a p53- independent manner that relied upon c-JUN, SP1, and JNK activity. Taken together, our results identify the critical signaling pathways activated by P14ARF to prevent vascular microthrombosis triggered by glioma cells. Stimulation of this pathway might be used as a therapeutic strategy to reduce aggressive phenotypes associated with necrotic tumors, including glioblastoma.