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Thioredoxin-1 Modulates Transcription of Cyclooxygenase-2 via Hypoxia-Inducible Factor-1 in Non–Small Cell Lung Cancer

Departments of ¹ Cancer Biology, ² Medicine (Hematology-Oncology), and ³ Pharmacology, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee

Requests for reprints: David P. Carbone, Vanderbilt-Ingram Cancer Center, 685 Preston Research Building, Nashville, TN 37232-6838. Phone: 615-936-3524; Fax: 615-936-3222; E-mail: d.carbone{at}vanderbilt.edu.

Hypoxic induction of gene expression occurs mainly via the hypoxia-inducible factor-1 (HIF-1) transcription factor and is a critical step in tumor growth. Cyclooxygenase-2 (COX-2) is commonly overexpressed in non–small cell lung cancer (NSCLC). In this study, we sought to determine the role of HIF-1 in the induction of COX-2 expression during hypoxia. Through sequence comparison of hypoxia-responsive genes, COX-2 promoter deletion analysis, and site-directed mutagenesis, we identified a hypoxia-responsive element within the COX-2 promoter that interacts with HIF-1 and underlies the mechanism of hypoxic activation of COX-2 in lung cancer cells. Proteomic analysis of NSCLC identified thioredoxin-1 as a redox protein overexpressed in NSCLC correlated with poor prognosis. We also show that thioredoxin-1 stabilizes HIF-1 to induce hypoxia-responsive genes under normoxic conditions. Our results identify two new mechanisms for regulation of COX-2 expression in NSCLC. (Cancer Res 2006; 66(1): 143-50)

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