Dataset Information

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

ABSTRACT: 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.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.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.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.

SUBMITTER: Lo HW

PROVIDER: S-EPMC2707832 | biostudies-literature | 2008 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Lo Hui-Wen HW Cao Xinyu X Zhu Hu H Ali-Osman Francis F

Clinical cancer research : an official journal of the American Association for Cancer Research 20081001 19

<h4>Purpose</h4>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.<h4>Experimental design</h4>Immunohistochemical staining and biochemical methods were used to examine the extent of STAT3 activation and EGFR expression in primary specimens an ...[more]

PMID: 18829483

Similar Datasets

Project description:BackgroundPediatric high-grade gliomas (pHGG) are the leading cause of cancer-related death during childhood. Due to their diffuse growth characteristics, chemoresistance and location behind the blood-brain barrier (BBB), the prognosis of pHGG has barely improved in the past decades. As such, there is a dire need for new therapies that circumvent those difficulties. Since aberrant expression of DNA damage-response associated Fanconi anemia proteins play a central role in the onset and therapy resistance of many cancers, we here investigated if FANCD2 depletion could sensitize pHGG to additional DNA damage.MethodsWe determined the capacity of celastrol, a BBB-penetrable compound that degrades FANCD2, to sensitize glioma cells to the archetypical DNA-crosslinking agent carboplatin in vitro in seven patient-derived pHGG models. In addition, we tested this drug combination in vivo in a patient-derived orthotopic pHGG xenograft model. Underlying mechanisms to drug response were investigated using mRNA expression profiling, western blotting, immunofluorescence, FANCD2 knockdown and DNA fiber assays.FindingsFANCD2 is overexpressed in HGGs and depletion of FANCD2 by celastrol synergises with carboplatin to induce cytotoxicity. Combination therapy prolongs survival of pHGG-bearing mice over monotherapy and control groups in vivo (P<0.05). In addition, our results suggest that celastrol treatment stalls ongoing replication forks, causing sensitivity to DNA-crosslinking in FANCD2-dependent glioma cells.InterpretationOur results show that depletion of FANCD2 acts as a chemo-sensitizing strategy in pHGG. Combination therapy using celastrol and carboplatin might serve as a clinically relevant strategy for the treatment of pHGG.FundingThis study was funded by a grant from the Children Cancer-Free Foundation (KIKA, project 210). The disclosed funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets