title: Suppression of mitochondrial respiration with auraptene inhibits the progression of renal cell carcinoma: involvement of HIF-1α degradation.
abstract: Renal cell carcinoma (RCC) progression resulting from the uncontrolled migration and enhanced angiogenesis is an obstacle to effective therapeutic intervention. Tumor metabolism has distinctive feature called Warburg effect, which enhances the aerobic glycolysis rapidly supplying the energy for migration of tumor. To manipulate this metabolic change characteristic of aggressive tumors, we utilized the citrus extract, auraptene, known as a mitochondrial inhibitor, testing its anticancer effects against the RCC4 cell line. We found that auraptene impaired RCC4 cell motility through reduction of mitochondrial respiration and glycolytic pathway-related genes. It also strongly disrupted VEGF-induced angiogenesis in vitro and in vivo. Hypoxia-inducible factor 1a (HIF-1a), a key regulator of cancer metabolism, migration and angiogenesis that is stably expressed in RCCs by virtue of a genetic mutation in the von Hippel-Lindau (VHL) tumor-suppressor protein, was impeded by auraptene, which blocked HIF-1a translation initiation without causing cytotoxicity. We suggest that blockade HIF-1a and reforming energy metabolism with auraptene is an effective approach for suspension RCC progression.
authors.affiliation: Department of Biochemistry, Chungnam National University School of Medicine, Daejeon, Republic of Korea, 301-747.
authors.forename: Yunseon
authors.initials: Y
authors.lastname: Jang
authors.affiliation: Department of Biochemistry, Chungnam National University School of Medicine, Daejeon, Republic of Korea, 301-747.
authors.forename: Jeongsu
authors.initials: J
authors.lastname: Han
authors.affiliation: Department of Biochemistry, Chungnam National University School of Medicine, Daejeon, Republic of Korea, 301-747.
authors.forename: Soo Jeong
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Department of Biochemistry, Chungnam National University School of Medicine, Daejeon, Republic of Korea, 301-747.
authors.forename: Jungim
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Biochemistry, Chungnam National University School of Medicine, Daejeon, Republic of Korea, 301-747.
authors.forename: Min Joung
authors.initials: MJ
authors.lastname: Lee
authors.affiliation: Department of Biochemistry, Chungnam National University School of Medicine, Daejeon, Republic of Korea, 301-747.
authors.forename: Soyeon
authors.initials: S
authors.lastname: Jeong
authors.affiliation: Department of Biochemistry, Chungnam National University School of Medicine, Daejeon, Republic of Korea, 301-747.|Research Institute for Medical Science, Chungnam National University School of Medicine, Daejeon, Republic of Korea, 301-747.
authors.forename: Min Jeong
authors.initials: MJ
authors.lastname: Ryu
authors.affiliation: R&D Center, KT&G Life Sciences, Suwon, Republic of Korea, 443-702.
authors.forename: Kang-Sik
authors.initials: KS
authors.lastname: Seo
authors.affiliation: Department of Pathology, Chungnam National University School of Medicine, Daejeon, Republic of Korea, 301-747.
authors.forename: Song-Yi
authors.initials: SY
authors.lastname: Choi
authors.affiliation: Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Republic of Korea, 301-747.
authors.forename: Minho
authors.initials: M
authors.lastname: Shong
authors.affiliation: Department of Biochemistry, Chungnam National University School of Medicine, Daejeon, Republic of Korea, 301-747.|Research Institute for Medical Science, Chungnam National University School of Medicine, Daejeon, Republic of Korea, 301-747.
authors.forename: Kyu
authors.initials: K
authors.lastname: Lim
authors.affiliation: Department of Biochemistry, Chungnam National University School of Medicine, Daejeon, Republic of Korea, 301-747.|Brain research institute, Chungnam National University School of Medicine, Daejeon, Republic of Korea, 301-747.
authors.forename: Jun Young
authors.initials: JY
authors.lastname: Heo
authors.affiliation: Department of Biochemistry, Chungnam National University School of Medicine, Daejeon, Republic of Korea, 301-747.|Research Institute for Medical Science, Chungnam National University School of Medicine, Daejeon, Republic of Korea, 301-747.
authors.forename: Gi Ryang
authors.initials: GR
authors.lastname: Kweon
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D019069:Cell Respiration / Q000187:drug effects; D003374:Coumarins / Q000494:pharmacology*; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004734:Energy Metabolism / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic; D006019:Glycolysis / Q000187:drug effects; D006367:HeLa Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D008819:Mice, Nude; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009154:Mutation; D009361:Neoplasm Invasiveness; D018919:Neovascularization, Physiologic / Q000187:drug effects; D059748:Proteolysis; D034622:RNA Interference; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D003374:Coumarins; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C105832:aurapten
keywords: HIF-1α; auraptene; eIF2α; mitochondrial respiration; renal cell carcinoma