Cross talk between mitochondria and superoxide generating NADPH oxidase in breast and ovarian tumors.

Reactive oxygen species (ROS) signal cascades involved in cell growth, cell death, mitogenesis, angiogenesis and carcinogenesis. ROS are produced as a byproduct of oxidative phosphorylation (OXPHOS) in the mitochondria. It is estimated that 2-4% of the oxygen consumed during OXPHOS is converted to ROS. Besides mitochondria, NADPH-oxidase 1 (Nox1) also generates a significant amount of ROS in the cell. In this paper, we tested the hypothesis that mitochondria control Nox 1 redox signaling and the loss of control of this signaling contributes to tumorigenesis. We analyzed Nox1 expression in a mitochondrial gene knockout (rho(0)) cell line and in the isogenic cybrid cell line in which mitochondrial genes were restored by transfer of wild type mitochondria into rho(0) cells. Our study revealed, for the first time, that the inactivation of mitochondrial genes leads to down-regulation of Nox1 and that the transfer of wild type mitochondrial genes restored the Nox1 expression to a level comparable to that in the parental cell line. Consistent with Nox1 down-regulation, we found that rho(0) cells contained low levels of superoxide anion and that superoxide levels reversed to parental levels in cybrid cells when Nox1 expression was restored by transfer of wild type mitochondria. Increasing mitochondrial superoxide levels also increased the expression of Nox1 in parental cells. Confocal microscopy studies revealed that Nox1 localizes in the mitochondria. Nox1 was highly expressed in breast (86%) and ovarian (71%) tumors and that its expression positively correlated with expression of cytochrome C oxidase encoded by mtDNA. Our study, described in this paper demonstrates the existence of cross talk between the mitochondria and NADPH oxidase. Furthermore, our studies suggest that mitochondria control Nox1 redox signaling and the loss of control of this signaling contributes to breast and ovarian tumorigenesis.
AuthorsMohamed Mokhtar Desouki, Mariola Kulawiec, Sanjay Bansal, Gokul M Das, Keshav K Singh
JournalCancer biology & therapy (Cancer Biol Ther) Vol. 4 Issue 12 Pg. 1367-73 (Dec 2005) ISSN: 1538-4047 [Print] United States
PMID16294028 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • DNA, Mitochondrial
  • Reactive Oxygen Species
  • NADPH Oxidase
  • superoxide-forming enzyme
  • Breast Neoplasms (metabolism, pathology)
  • Carcinoma (pathology)
  • Cell Line, Tumor
  • DNA, Mitochondrial (metabolism)
  • Female
  • Gene Expression Regulation, Enzymologic
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Hybrid Cells (cytology, metabolism)
  • Mitochondria (genetics, metabolism)
  • NADPH Oxidase (metabolism)
  • Ovarian Neoplasms (metabolism, pathology)
  • Reactive Oxygen Species (metabolism)
  • Signal Transduction

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