title: Primary clear cell renal carcinoma cells display minimal mitochondrial respiratory capacity resulting in pronounced sensitivity to glycolytic inhibition by 3-Bromopyruvate.
abstract: Changes of cellular metabolism are an integral property of the malignant potential of most cancer cells. Already in the 1930s, Otto Warburg observed that tumor cells preferably utilize glycolysis and lactate fermentation for energy production, rather than the mitochondrial oxidative phosphorylation dominating in normal cells, a phenomenon today known as the Warburg effect. Even though many tumor types display a high degree of aerobic glycolysis, they still retain the activity of other energy-producing metabolic pathways. One exception seems to be the clear cell variant of renal cell carcinoma, ccRCC, where the activity of most other pathways than that of glycolysis has been shown to be reduced. This makes ccRCC a promising candidate for the use of glycolytic inhibitors in treatment of the disease. However, few studies have so far addressed this issue. In this report, we show a strikingly reduced mitochondrial respiratory capacity of primary human ccRCC cells, resulting in enhanced sensitivity to glycolytic inhibition by 3-Bromopyruvate (3BrPA). This effect was largely absent in established ccRCC cell lines, a finding that highlights the importance of using biologically relevant models in the search for new candidate cancer therapies. 3BrPA markedly reduced ATP production in primary ccRCC cells, followed by cell death. Our data suggest that glycolytic inhibitors such as 3BrPA, that has been shown to be well tolerated in vivo, should be further analyzed for the possible development of selective treatment strategies for patients with ccRCC.
authors.affiliation: Department of Laboratory Medicine Malmö, Center for Molecular Pathology, Lund University, Skåne University Hospital, Malmö, Sweden.
authors.forename: H
authors.initials: H
authors.lastname: Nilsson
authors.affiliation: Department of Laboratory Medicine Lund, Division of Translational Cancer Research, Lund University, Lund, Sweden.
authors.forename: D
authors.initials: D
authors.lastname: Lindgren
authors.affiliation: Department of Urology, Clinical Sciences Malmö, Lund University, Malmö, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Mandahl Forsberg
authors.affiliation: Department of Clinical Sciences, Unit of Molecular Metabolism, Lund University Diabetes Centre, Malmö, Sweden.
authors.forename: H
authors.initials: H
authors.lastname: Mulder
authors.affiliation: Department of Laboratory Medicine Lund, Division of Translational Cancer Research, Lund University, Lund, Sweden.
authors.forename: H
authors.initials: H
authors.lastname: Axelson
authors.affiliation: Department of Laboratory Medicine Malmö, Center for Molecular Pathology, Lund University, Skåne University Hospital, Malmö, Sweden.
authors.forename: M E
authors.initials: ME
authors.lastname: Johansson
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000473:pathology* / Q000648:ultrastructure; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019069:Cell Respiration / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006019:Glycolysis / Q000187:drug effects*; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics / Q000473:pathology* / Q000648:ultrastructure; D007773:Lactates / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D027501:Monocarboxylic Acid Transporters / Q000235:genetics / Q000378:metabolism; D011773:Pyruvates / Q000494:pharmacology*; D027981:Symporters / Q000235:genetics / Q000378:metabolism; D000099233:Monocarboxylate Transport Protein 1
chemical_list: D000255:Adenosine Triphosphate; D007773:Lactates; D027501:Monocarboxylic Acid Transporters; D011773:Pyruvates; D027981:Symporters; D000099233:Monocarboxylate Transport Protein 1; C017092:bromopyruvate