Mitochondrial cytochrome B gene mutation promotes tumor growth in bladder cancer.
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.
Dasgupta
Santanu
S
Department of Otolaryngology-Head and Neck Surgery, Division of Head and Neck Cancer Research, Johns Hopkins University, Baltimore, Maryland 21231, USA.
Hoque
Mohammad Obaidul
MO
Upadhyay
Sunil
S
Sidransky
David
D
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002295:Carcinoma, Transitional Cell / Q000098:blood supply / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion / Q000235:genetics; D002453:Cell Cycle / Q000235:genetics; D048708:Cell Growth Processes / Q000235:genetics; D045303:Cytochromes b / Q000096:biosynthesis / Q000235:genetics*; D004272:DNA, Mitochondrial / Q000235:genetics; D005260:Female; D017353:Gene Deletion; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D013154:Spleen / Q000378:metabolism / Q000473:pathology; D014162:Transfection; D001749:Urinary Bladder Neoplasms / Q000098:blood supply / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis / Q000235:genetics
C494827:Bax protein, mouse; D004272:DNA, Mitochondrial; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D051028:bcl-2-Associated X Protein; D045303:Cytochromes b