P14ARF suppresses tumor-induced thrombosis by regulating the tissue factor pathway

Abdessamad Zerrouqi, Beata Pyrzynska, Daniel J. Brat, Erwin G. Van Meir*

*Corresponding author for this work

Research output: Contribution to journalArticle

11 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1371-1378
Number of pages8
JournalCancer Research
Volume74
Issue number5
DOIs
StatePublished - Mar 1 2014

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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