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Targeting the hypoxia inducible factor pathway with mitochondrial uncouplers

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Abstract

Hypoxia inducible factor-1 (HIF-1) is central to most adaptation responses of tumors to hypoxia, and consists of a hypoxia inducible HIF-1α or -2α subunit, and a constitutively expressed HIF-1β subunit. Previously, mitochondrial uncouplers, rottlerin and FCCP, were shown to increase the rate of cellular O2 consumption. In this study, we determined that mitochondrial uncouplers, rottlerin and FCCP, significantly decreased hypoxic as well as normoxic HIF-1 transcriptional activity which was in part mediated by down-regulation of the oxygen labile HIF-1α and HIF-2α protein levels in PC-3 and DU-145 prostate cancer cells. Our results also revealed that mitochondrial uncouplers decreased the expression of HIF target genes, VEGF and VEGF receptor-2. Taken together, our results indicate that functional mitochondria are important in HIF-1α and HIF-2α protein stability and transcriptional activity during normoxia as well as in hypoxia, and that mitochondrial uncouplers may be useful in the inhibition of HIF pathway in tumors.

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Acknowledgments

We thank Dr. Peter RatCliffe and Dr. Richard P. DiAugustine for providing us with the plasmid constructs. This work was supported by NIH grant # 1R21CA102382 to M. H. Kim.

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  1. Department of Molecular Biology and Immunology, University of North Texas Health Science Center, Fort Worth, TX, 76107, USA

    Rusha Thomas & Myoung H. Kim

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  1. Rusha Thomas
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  2. Myoung H. Kim
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Correspondence to Myoung H. Kim.

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Thomas, R., Kim, M.H. Targeting the hypoxia inducible factor pathway with mitochondrial uncouplers. Mol Cell Biochem 296, 35–44 (2007). https://doi.org/10.1007/s11010-006-9295-3

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  • DOI: https://doi.org/10.1007/s11010-006-9295-3

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