Metastasis: Trading in mitochondria
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Although mutations in mitochondrial DNA (mtDNA) occur with high fre- quency in human tumours, their role, if any, in tumorigenesis is unclear. In their recent Science article, Ishikawa et al. describe how exchanging the mtDNA between mouse tumour cell lines revealed mutations that increase the metastatic potential of tumour cells. The authors used the mouse tumour cell lines P29, which has low metastatic potential, and A11, which has high metastatic potential, and created ‘cybrid’ cell lines by reciprocal exchange of the complete mitochon- drial genomes. A11 cells were found to have decreased complex I (NADH dehydrogenase) activity compared with P29, a result also observed in the cybrids with A11 mtDNA but not those with P29 mtDNA, indicating that the complex I defects are attrib- utable to mutations in the mitochon- drial, not nuclear, DNA. Inoculation in mice demonstrated that metastatic potential was increased in the cybrids with the A11 mtDNA and decreased in those with P29 mtDNA. However, similar transfer of A11 mtDNA to non-transformed cells did not result in tumorigenicity, suggesting that the effect of the mitochondrial mutations in A11 is limited to the development of metastases. To determine the mutations responsible, Ishikawa and col- leagues compared the two mtDNA sequences, finding a missense mutation (G13997A) in Nd6 (NADH dehydrogenase subunit 6) exclusively within the A11 mtDNA. A similar set of experiments in the low-metastatic cell line B82 and its high-metastatic derivative B82M revealed a frame-shift mutation within the same gene (13885insC). So, how do these mutations exert their effect? In the cybrids with mutated A11 mtDNA but not those with P29 mtDNA, increased production of reactive oxygen species (ROS) was observed. Moreover, upregulation of the nuclear genes Mcl1, Hif1a and Veg f was found to be cotransferred with the mutated mtDNA, and downregulation of MCL1 with small interfering RNA reduced metastasis in P29mtA11 cybrids. Treatment of the cells with ROS scavengers was found to reduce levels of ROS, downregulate MCL1 and reduce metastatic potential, but without reduc- ing glycolytic activity. Thus the increased metastatic activity in the ROS-overproducing mutants is caused by a mechanism involving upregulation of MCL1, but not upregulation of glycolysis. In all cell lines tested, including human, transfer of mutant mtDNA associated with ROS overproduction significantly increased metastatic potential, so the possibility of ROS scavengers as therapeutic suppres- sors of metastasis merits further investigation. Isobel Barry ORIGINAL RESEARCH PAPER Ishikawa, K. et al. ROS-generating mitochondrial DNA mutations can regulate tumor cell metastasis. Science 320, 661–664 (2008) METASTASIS Trading in mitochondria ImageSource RESEARCH HIGHLIGHTS NATURE REVIEWS | CANCER VOLUME 8 | JUNE 2008 © 2008 Nature Publishing Group
Transcript of Metastasis: Trading in mitochondria
Although mutations in mitochondrial DNA (mtDNA) occur with high fre-quency in human tumours, their role, if any, in tumorigenesis is unclear. In their recent Science article, Ishikawa et al. describe how exchanging the mtDNA between mouse tumour cell lines revealed mutations that increase the metastatic potential of tumour cells.
The authors used the mouse tumour cell lines P29, which has low metastatic potential, and A11, which has high metastatic potential, and created ‘cybrid’ cell lines by reciprocal exchange of the complete mitochon-drial genomes. A11 cells were found to have decreased complex I (NADH dehydrogenase) activity compared with P29, a result also observed in the cybrids with A11 mtDNA but not those with P29 mtDNA, indicating that the complex I defects are attrib-utable to mutations in the mitochon-drial, not nuclear, DNA. Inoculation in mice demonstrated that metastatic potential was increased in the cybrids with the A11 mtDNA and decreased in those with P29 mtDNA. However, similar transfer of A11 mtDNA to non-transformed cells did not result in tumorigenicity, suggesting that the effect of the mitochondrial mutations in A11 is limited to the development of metastases.
To determine the mutations responsible, Ishikawa and col-leagues compared the two mtDNA sequences, finding a missense mutation (G13997A) in Nd6 (NADH dehydrogenase subunit 6) exclusively within the A11 mtDNA. A similar set of experiments in the low-metastatic cell line B82 and its high-metastatic derivative B82M revealed a frame-shift mutation within the same gene (13885insC).
So, how do these mutations exert their effect? In the cybrids with mutated A11 mtDNA but not those with P29 mtDNA, increased production of reactive oxygen species (ROS) was observed. Moreover, upregulation of the nuclear genes Mcl1, Hif1a and Vegf was found to be cotransferred with the mutated mtDNA, and downregulation of MCL1 with small interfering RNA reduced metastasis in P29mtA11 cybrids. Treatment of the cells with ROS scavengers was found to reduce levels of ROS, downregulate MCL1 and reduce metastatic potential, but without reduc-ing glycolytic activity. Thus the increased metastatic activity in the ROS-overproducing mutants is caused by a mechanism involving upregulation of MCL1, but not upregulation of glycolysis.
In all cell lines tested, including human, transfer of mutant mtDNA associated with ROS overproduction significantly increased metastatic potential, so the possibility of ROS scavengers as therapeutic suppres-sors of metastasis merits further investigation.
Isobel Barry
ORIGINAL RESEARCH PAPER Ishikawa, K. et al. ROS-generating mitochondrial DNA mutations can regulate tumor cell metastasis. Science 320, 661–664 (2008)
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Trading in mitochondria
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NATuRe RevIewS | cancer vOLuMe 8 | juNe 2008
© 2008 Nature Publishing Group
