EGFR induces expression of IRF‐1 via STAT1 and STAT3 activation leading to growth arrest of human cancer cells

Abstract

Recently, we reported that epidermal growth factor receptor (EGFR) induce expression of a module of genes known to be inducible by interferons and particularly interferon-c. Here we show that the module is tightly regulated by EGFR in the 2 human cancer cell lines that overexpress EGFR, A431 and HN5. The module of genes included the tumor suppressor IRF-1, which was used as a prototypical member to further investigate the regulation and function of the module. Ligand-activated EGFR induce expression of IRF-1 via phosphorylation of STAT1 and STAT3. In contrast, cells expressing the constitutively active cancer specific receptor EGFRvIII are unable to mediate phosphorylation of these STATs and thereby incapable of inducing IRF-1. We also demonstrate that IRF-1 is expressed in an EGF dose-dependent manner, which correlates with inhibition of cell proliferation, and that the regulation of IRF-1 is partially dependent on intracellular Src family kinase activity. Treatment with the dual specific Abl/cSrc kinase inhibitor AZD0530 significantly reduces the growth inhibitory effect of high EGF concentrations, signifying that EGFR induced IRF-1 is responsible for the observed growth inhibition. In addition, we show that media from these EGF treated cancer cells upregulate the activation marker CD69 on both B-cells and T-cells in peripheral blood. Taken together, these results suggest that cells acquiring sustained high activity of oncogenes such as EGFR are able to activate genes, whose products mediate growth arrest and activate immune effector cells, and which potentially could be involved in alerting the immune system in vivo leading to elimination of the transformed cells. ' 2007 Wiley-Liss, Inc.

Transfected Poly(I:C) Activates Different dsRNA Receptors, Leading to Apoptosis or Immunoadjuvant Response in Androgen-independent Prostate Cancer Cells

“…The role of the Src pathway downstream of growth factors is well known. In fact, Src involvement in PDGF-and EGF-mediated tyrosine phosphorylation of STAT1 and STAT3 has been reported in tumor and normal cells with different biological activity (48,49). In this report, we show for the first time the involvement of the TLR3/Src/STAT1 pathway in mediating in- …”

E2F3a Is Critically Involved in Epidermal Growth Factor Receptor–Directed Proliferation in Ovarian Cancer

“…The observation that of the various EGFR downstream pathways only inhibition of the JAK/STAT1/3 pathway revealed changes in E2F3a expression in terms of an E2F3a upregulation (Fig. 4D), together with the knowledge that JAK/ STAT1/3 participates at least in the regulation of IRF-1 expression (27), gave rise to the hypothesis that IRF-1 could act as a repressor and IRF-2 as an activator of E2F3a expression. On the other hand, VDR is not a known component of the JAK/STAT1/3 pathway, and furthermore, treatment of ovarian cancer cell lines with 1α, 25-dihydroxyvitamin D 3 , the most active metabolite of vitamin D 3 , did not affect E2F3a mRNA levels.…”

Newly Synthesized ‘Hidabeni’ Chalcone Derivatives Potently Suppress LPS-Induced NO Production <i>via</i> Inhibition of STAT1, but Not NF-κB, JNK, and p38, Pathways in Microglia

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