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Author Notes:

Corresponding author. Mailing address: Dept. of Radiation Oncology, Emory University, 1365 Clifton Road, NE, Suite CT-104, Atlanta, GA 30322. Phone: (404) 778-2161. Fax: (404) 778-4139. hgshu@emory.edu.

We thank P. Raychaudhuri for providing pCMV-T7FOXM1 and 6×FOX-luciferase reporter, Y. Feng for providing pCSrcA-HA14, T.J. Murphy for providing pTJ105 (MuLV luciferase vector), and C. Hadjipanayis for providing lysates from U87MG control and EGFRvIII-expressing cells.

Authors' Contributions: Conception and design: K. Xu, H.-K.G. Shu Development of methodology: K. Xu, H.-K.G. Shu Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): K. Xu, H.-K.G. Shu Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): K. Xu, H.-K.G. Shu Writing, review, and/or revision of the manuscript: K. Xu, H.-K.G. Shu Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): K. Xu, H.-K.G. Shu Study supervision: H.-K.G. Shu

Conflict of Interest: None.

Subjects:

Research Funding:

This work was supported, in part, by a Cancer Center grant from the National Cancer Institute (P30-CA138292).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Keywords:

  • cyclooxygenase-2
  • FOXM1
  • Sp1
  • epidermal growth factor receptor
  • glioma

Journal Title:

Molecular Cancer Research

Volume:

Volume 11, Number 8

Publisher:

, Pages 875-886

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Cyclooxygenase-2 (COX-2) is linked to worse prognosis in patients with malignant gliomas and other tumor types. Amplification/overexpression of epidermal growth factor receptor (EGFR) is commonly seen in these tumors. We have previously shown that EGFR signaling, through activation of p38-mitogen activated protein kinase (MAPK), protein kinase C-δ (PKC-δ), and Sp1, plays an important role in the regulation of COX-2 expression in glioma cells. Here, we report that the Src kinase also has a role in this signaling cascade upstream of p38-MAPK/PKC-δ. In addition, more detailed analysis revealed the involvement of FOXM1, a member of the forkhead box family of transcriptional activators, in EGF-dependent COX-2 induction. FOXM1 protein levels increase after stimulation with EGF although its role in modulating COX-2 expression does not depend on this increase. While a conventional FOXM1 responsive element resides in a distal region (−2872/−2539 relative to the transcriptional start site) of the COX-2 promoter, this is not required for EGF-dependent induction of COX-2. Instead, FOXM1 is capable of interacting with Sp1 at the Sp1 binding site (−245/−240 relative to the start site) of the COX-2 promoter and appears to act in cooperation with Sp1 to mediate EGF-induced COX-2 expression. Definition of this novel interaction provides us with a clearer understanding of the mechanistic basis for the induction of COX-2 with EGF and guides our evaluation of potential newer therapeutic targets that have relevance in this disease.

Copyright information:

© 2013 American Association for Cancer Research.

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