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Research Articles: Therapeutics, Targets, and Development

Photodynamic therapy mediates the oxygen-independent activation of hypoxia-inducible factor 1

Departments of ¹ Imaging Sciences and ² Microbiology and Immunology, University of Rochester Medical Center, and ³ Department of Physics and Astronomy, University of Rochester, Rochester, New York

Requests for reprints: Thomas H. Foster, Department of Imaging Sciences, University of Rochester, 601 Elmwood Avenue, Box 648, Rochester, NY 14642. Phone: 585-275-1347. E-mail: thomas.foster{at}rochester.edu

Abstract

Photodynamic therapy (PDT) induces the expression of the hypoxia-inducible factor 1 (HIF-1) subunit of the HIF-1 transcription factor and its target genes in vitro and in vivo. PDT also induces the expression of the enzyme cyclooxygenase-2 and its metabolite, prostaglandin E₂ (PGE₂). PGE₂ and hypoxia act independently and synergistically to increase HIF-1 accumulation and nuclear translocation. To examine the expression of HIF-1 target genes in response to PDT-mediated oxidative stress and PGE₂ under normoxic conditions, we established EMT6 cells transfected with a plasmid consisting of a hypoxia response element promoter and a downstream gene encoding for green fluorescent protein (GFP). To examine the temporal kinetics of HIF-1 nuclear translocation in response to PDT, we transfected a second line of EMT6 cells with a GFP-tagged HIF-1 fusion vector. Cell monolayers were incubated with 1 µg mL^–1 Photofrin for 24 h and irradiated with fluences of 1, 2.5, and 5 J cm^–2. Direct measurement of oxygen concentration during irradiation confirmed that cells remained well oxygenated. Cells were also exposed to 1 and 10 µmol/L PGE₂ for 3 h. In normoxic conditions, Photofrin, PDT, and PGE₂ treatment activated HIF-1 and induced its nuclear translocation. Maximal Photofrin-PDT–mediated HIF-1 activation was intermediate in magnitude between that induced by PGE₂ and that by the hypoxia mimic cobalt chloride. This work establishes that PDT induces significant activation of the HIF-1 pathway in the absence of hypoxia and supports the interpretation that the induction of HIF-1 target genes by PDT may be mediated, at least in part, by the prostaglandin pathway. [Mol Cancer Ther 2006;5(12):3268–74]

Grant support: U.S. NIH grant CA68409 awarded by the National Cancer Institute.

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.

⁴ http://rsb.info.nih.gov/ij/.

Received 7/18/06; revised 10/ 6/06; accepted 10/27/06.