Mitochondrial cytochrome B gene mutation promotes tumor growth in bladder cancer

Cancer Res. 2008 Feb 1;68(3):700-6. doi: 10.1158/0008-5472.CAN-07-5532.

Abstract

Mitochondria-encoded Cytochrome B (CYTB) gene mutations were reported in different cancers, but the effect of these mutations on cellular metabolism and growth is unknown. In a murine xenograft and human model of bladder cancer, we show the functional effect of overexpression of a 21-bp deletion mutation (mt) of CYTB. Overexpression of mtCYTB generated increased reactive oxygen species (ROS) accompanied by increased oxygen consumption and lactate production. MtCYTB overexpression induced significant tumor growth in vitro and in vivo by triggering rapid cell cycle progression through up-regulation of the nuclear factor-kappa B2 signaling pathway. Tumor-generated ROS induced in vitro lysis of normal splenocytes. Thus, we present physiologic and functional evidence for the role of a bona fide mitochondrial gene mutation in cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Carcinoma, Transitional Cell / blood supply
  • Carcinoma, Transitional Cell / genetics*
  • Carcinoma, Transitional Cell / metabolism
  • Carcinoma, Transitional Cell / pathology
  • Cell Adhesion / genetics
  • Cell Cycle / genetics
  • Cell Growth Processes / genetics
  • Cytochromes b / biosynthesis
  • Cytochromes b / genetics*
  • DNA, Mitochondrial / genetics
  • Female
  • Gene Deletion*
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria / genetics
  • Mitochondria / metabolism
  • NF-kappa B / metabolism
  • Neoplasm Invasiveness
  • Neovascularization, Pathologic / genetics
  • Proto-Oncogene Proteins c-bcl-2 / biosynthesis
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Reactive Oxygen Species / metabolism
  • Spleen / metabolism
  • Spleen / pathology
  • Transfection
  • Urinary Bladder Neoplasms / blood supply
  • Urinary Bladder Neoplasms / genetics*
  • Urinary Bladder Neoplasms / metabolism
  • Urinary Bladder Neoplasms / pathology
  • bcl-2-Associated X Protein / biosynthesis
  • bcl-2-Associated X Protein / genetics

Substances

  • Bax protein, mouse
  • DNA, Mitochondrial
  • NF-kappa B
  • Proto-Oncogene Proteins c-bcl-2
  • Reactive Oxygen Species
  • bcl-2-Associated X Protein
  • Cytochromes b