title: UCP-3 uncoupling protein confers hypoxia resistance to renal epithelial cells and is upregulated in renal cell carcinoma.
abstract: Tumor cells can adapt to a hostile environment with reduced oxygen supply. The present study aimed to identify mechanisms that confer hypoxia resistance. Partially hypoxia/reoxygenation (H/R)-resistant proximal tubular (PT) cells were selected by exposing PT cultures to repetitive cycles of H/R. Thereafter, H/R-induced changes in mRNA and protein expression, inner mitochondrial membrane potential (ΔΨ(m)), formation of superoxide, and cell death were compared between H/R-adapted and control PT cultures. As a result, H/R-adapted PT cells exhibited lower H/R-induced hyperpolarization of ΔΨ(m) and produced less superoxide than the control cultures. Consequently, H/R triggered ΔΨ(m) break-down and DNA degradation in a lower percentage of H/R-adapted than control PT cells. Moreover, H/R induced upregulation of mitochondrial uncoupling protein-3 (UCP-3) in H/R-adapted PT but not in control cultures. In addition, ionizing radiation killed a lower percentage of H/R-adapted as compared to control cells suggestive of an H/R-radiation cross-resistance developed by the selection procedure. Knockdown of UCP-3 decreased H/R- and radioresitance of the H/R-adapted cells. Finally, UCP-3 protein abundance of PT-derived clear cell renal cell carcinoma and normal renal tissue was compared in human specimens indicating upregulation of UCP-3 during tumor development. Combined, our data suggest functional significance of UCP-3 for H/R resistance.
authors: Department of Radiation Oncology, University of Tübingen Germany.
authors: Norbert
authors: N
authors: Braun
authors: Department of Radiation Oncology, University of Tübingen Germany.
authors: Dominik
authors: D
authors: Klumpp
authors: Department of Urology, University of Tübingen, Germany.
authors: Jörg
authors: J
authors: Hennenlotter
authors: Department of Urology, University of Tübingen, Germany.
authors: Jens
authors: J
authors: Bedke
authors: Department of Faculté de Médecine, Université de Nice-Sophia Antipolis, Nice, France.
authors: Christophe
authors: C
authors: Duranton
authors: Department of Radiation Oncology, University of Tübingen Germany.
authors: Martin
authors: M
authors: Bleif
authors: Department of Radiation Oncology, University of Tübingen Germany.
authors: Stephan M
authors: SM
authors: Huber
mesh_terms: D000368:Aged; D002292:Carcinoma, Renal Cell / Q000378:metabolism* / Q000473:pathology*; D015687:Cell Hypoxia; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D007473:Ion Channels / Q000378:metabolism*; D007680:Kidney Neoplasms / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D024101:Mitochondrial Proteins / Q000378:metabolism*; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D000071247:Uncoupling Protein 3; D015854:Up-Regulation
chemical_list: D007473:Ion Channels; D024101:Mitochondrial Proteins; C000604392:UCP3 protein, human; D000071247:Uncoupling Protein 3; D010100:Oxygen