title: Therapeutic inhibition of mitochondrial function induces cell death in starvation-resistant renal cell carcinomas.
abstract: Renal cell carcinomas (RCC) have two types of cells for carbon metabolism and for cell signaling under nutrient-deprivation conditions, namely starvation-resistant and starvation-sensitive cells. Here, we evaluated the mitochondrial characteristics of these cell types and found that the resistant type possessed higher activities for both mitochondrial oxidative phosphorylation and glycolysis than the sensitive types. These higher activities were supported by the stored carbon, lipid and carbohydrate sources, and by a low level of mitochondrial reactive oxygen species (ROS) due to sustained SOD2 expression in the resistant RCC cells. In metastatic RCC cases, higher SOD2 expression was associated with a significantly shorter survival period. We found that treatment with the drugs etomoxir and buformin significantly reduced mitochondrial oxidative phosphorylation and induced cell death under glucose-deprivation conditions in starvation-resistant RCC cells. Our data suggest that inhibitory targeting of mitochondria might offer an effective therapeutic option for metastatic RCC that is resistant to current treatments.
authors.affiliation: Central Reseach Laboratory, Shiga University of Medical Science, Tsukinowa-cho, Seta, Otsu, Shiga 520-2192, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Isono
authors.affiliation: Departments of Clinical Laboratory Medicine, Shiga University of Medical Science, Otsu, Shiga 520-2192, Japan.
authors.forename: Tokuhiro
authors.initials: T
authors.lastname: Chano
authors.affiliation: Departments of Urology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Yonese
authors.affiliation: Departments of Urology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yuasa
mesh_terms: D000143:Acids / Q000378:metabolism; D002026:Buformin / Q000494:pharmacology / Q000627:therapeutic use; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000473:pathology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D004852:Epoxy Compounds / Q000494:pharmacology / Q000627:therapeutic use; D005434:Flow Cytometry; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D007700:Kinetics; D008055:Lipids / Q000737:chemistry; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009362:Neoplasm Metastasis; D010085:Oxidative Phosphorylation / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D011379:Prognosis; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: D000143:Acids; D004852:Epoxy Compounds; D008055:Lipids; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase; C054207:etomoxir; D002026:Buformin