Constitutively activated STAT3 frequently coexpresses with epidermal growth factor receptor in high-grade gliomas and targeting STAT3 sensitizes them to Iressa and alkylators.

Abstract

PURPOSE:

The goals of this study are to elucidate the relationship of the oncogenic transcription factor signal transducer and activator of transcription 3 (STAT3) with glioma aggressiveness and to understand the role of high STAT3 activity in the resistance of malignant gliomas and medulloblastomas to chemotherapy.

EXPERIMENTAL DESIGN:

Immunohistochemical staining and biochemical methods were used to examine the extent of STAT3 activation and EGFR expression in primary specimens and cell lines, respectively. Cellular response to drug treatments was determined using cell cytotoxicity and clonogenic growth assays.

RESULTS:

We found STAT3 to be constitutively activated in 60% of primary high-grade/malignant gliomas and the extent of activation correlated positively with glioma grade. High levels of activated/phosphorylated STAT3 were also present in cultured human malignant glioma and medulloblastoma cells. Three STAT3-activating kinases, Janus-activated kinase 2 (JAK2), EGFR, and EGFRvIII, contributed to STAT3 activation. An inhibitor to JAK2/STAT3, JSI-124, significantly reduced expression of STAT3 target genes, suppressed cancer cell growth, and induced apoptosis. Furthermore, we found that STAT3 constitutive activation coexisted with EGFR expression in 27.2% of primary high-grade/malignant gliomas and such coexpression correlated positively with glioma grade. Combination of an anti-EGFR agent Iressa and a JAK2/STAT3 inhibitor synergistically suppressed STAT3 activation and potently killed glioblastoma cell lines that expressed EGFR or EGFRvIII. JSI-124 also sensitized malignant glioma and medulloblastoma cells to temozolomide, 1,3-bis(2-chloroethyl)-1-nitrosourea, and cisplatin in which a synergism existed between JSI-124 and cisplatin.

CONCLUSION:

STAT3 constitutive activation, alone and in concurrence with EGFR expression, plays an important role in high-grade/malignant gliomas and targeting STAT3/JAK2 sensitizes these tumors to anti-EGFR and alkylating agents.

• Authors: Hui-Wen Lo, Xinyu Cao, Hu Zhu, Francis Ali-Osman
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 14 Issue 19 Pg. 6042-54 (Oct 01 2008) ISSN: 1078-0432 [Print] United States
• PMID: 18829483 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Alkylating Agents
• Antineoplastic Agents
• Quinazolines
• STAT3 Transcription Factor
• STAT3 protein, human
• ErbB Receptors
• JAK2 protein, human
• Janus Kinase 2
• Gefitinib

Topics

• Alkylating Agents (pharmacology)
• Animals
• Antineoplastic Agents (pharmacology)
• Brain Neoplasms (metabolism)
• Cell Line, Tumor
• DNA Damage
• ErbB Receptors (biosynthesis)
• Gefitinib
• Gene Expression Regulation, Neoplastic
• Glioma (metabolism)
• Humans
• Inhibitory Concentration 50
• Janus Kinase 2 (metabolism)
• Mice
• Quinazolines (pharmacology)
• STAT3 Transcription Factor (biosynthesis, genetics)