GLI2 transcription factor mediates cytokine cross-talk in the tumor microenvironment

Sherine F. Elsawa, Luciana L. Almada, Steven C. Ziesmer, Anne J. Novak, Thomas E. Witzig, Stephen M. Ansell, Martin E. Fernandez-Zapico

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

Tumor cells interact with their surrounding microenvironment to survive and persist within the host. Cytokines play a key role in regulating this crosstalk between malignant cells and surrounding cells in the microenvironment. Although this phenomenon is clearly established, the molecular mechanisms mediating this cellular event remain elusive. Here, using as a model bone marrow stromal cells, we describe a novel signaling mechanism initiated by CCL5 in these cells leading to up-regulation of immunoglobulin secretion by malignant B cells. CCL5 increases IL-6 expression and secretion in bone marrow stromal cells. IL-6 in turn induces Ig secretion by malignant B cells. Analysis of the mechanism reveals that CCL5 signaling induces GLI2 through a PI3K-AKT-IκBα-p65 pathway and requires GLI2 transcriptional activity to modulate IL-6 expression and Ig secretion in vitro and in vivo. Together, these results identify a novel signaling pathway mediating the stromal-cancer cell interactions, leading to increased Ig production by malignant cells.

Original languageEnglish (US)
Pages (from-to)21524-21534
Number of pages11
JournalJournal of Biological Chemistry
Volume286
Issue number24
DOIs
StatePublished - Jun 17 2011

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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