Faculty Collaboration Database

Epidermal growth factor receptor-independent constitutive activation of STAT3 in head and neck squamous cell carcinoma is mediated by the autocrine/paracrine stimulation of the interleukin 6/gp130 cytokine system. Cancer Res 2003 Jun 01;63(11):2948-56

Date

06/05/2003

Pubmed ID

12782602

Scopus ID

2-s2.0-0038581774 (requires institutional sign-in at Scopus site)   246 Citations

Abstract

The aberrant growth of head and neck squamous cell carcinoma (HNSCC) is often associated with the constitutive activation of signal-transducer-and-activator-of-transcription-3 (STAT3), which is believed to result from the persistent stimulation of EGF receptors that are highly expressed in squamous cell carcinoma (SCC) cells. To investigate the mechanism underlying STAT3 deregulation in HNSCC, we examined the interplay of the STAT3 and epidermal growth factor receptor (EGFR) signaling pathways using a panel of HNSCC cell lines. Although STAT3 was active in most HNSCC cell lines, only 3 of 10 HNSCC cell lines were moderately to strongly positive for activated EGFR. Even in the EGFR-positive cell lines, STAT3 activation was not dependent on EGFR activation, as STAT3 tyrosine phosphorylation levels persisted after treatment with AG1478, a chemical inhibitor of EGFR activity. Furthermore, we found that conditioned medium harvested from HNSCC cells could induce STAT3 tyrosine phosphorylation in immortalized keratinocytes regardless of the status of EGFR signaling. In contrast, blocking the cytokine gp130 coreceptor abolished STAT3 tyrosine phosphorylation in HNSCC cells and that induced by the conditioned medium. Immunodepletion studies suggested interleukin 6 (IL6) as the major autocrine/paracrine factor for STAT3 activation, which coincided with high levels of secretion of IL6 into the culture medium by these cancer cells. Treatment with a specific inhibitor of Janus kinase, AG490, in HNSCC cells led to a reduction of active STAT3 and caused significant growth retardation and apoptosis. Thus, constitutive activation of STAT3 in HNSCC may use an autocrine/paracrine-activating loop mediated by IL6 and other cytokines acting through the gp130 receptor family, which may confer both proliferative and survival potential in this malignancy.

Author List

Sriuranpong V, Park JI, Amornphimoltham P, Patel V, Nelkin BD, Gutkind JS

Author

Jong-In Park PhD Professor in the Biochemistry department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Antigens, CD
Apoptosis
Carcinoma, Squamous Cell
Cell Division
Cell Survival
Cytokine Receptor gp130
DNA-Binding Proteins
Enzyme Inhibitors
ErbB Receptors
Head and Neck Neoplasms
Humans
Interleukin-6
Membrane Glycoproteins
Phosphorylation
Protein-Tyrosine Kinases
Quinazolines
STAT3 Transcription Factor
Signal Transduction
Trans-Activators
Tumor Cells, Cultured
Tyrphostins