Diminished tumorigenic phenotype after depletion of mitochondrial DNA.
Modulation of tumorigenicity has been considered to be a reflection of the (nuclear) genetic and cellular aberrations present in tumor cells. Recent studies have suggested that cytoplasmic elements can also contribute to the malignant phenotype of cancer, and that mitochondria may be important in this process. We, therefore, undertook a study to evaluate the effects of depletion of functional mitochondria on the tumorigenic phenotype. Brain and breast tumor cells were depleted of mitochondrial DNA [rho(-)] by treatment with ethidium bromide. These rho(-) respiratory-deficient cells showed a distinct change in the tumorigenic phenotype, including loss of ability to grow in an anchorage-independent fashion and, interestingly, a substantial increase in sensitivity to cytotoxic drugs (1,3-bis-chloroethyl-1-nitrosourea and cis-diamminedichloroplatinum(II)). Reversion to the tumorigenic phenotype was accomplished with transfer of normal mitochondria into the diminished tumorigenic rho(-) cells. No changes in expression of the apoptosis genes bcl-2 and bax, nor the drug resistance genes mdr1, mrp, or O6-alkyltransferase was found in any of the cell types (de novo, rho(-), or cybrid). Further, the type of cell death remained the same, i.e., cells with and without mitochondria underwent apoptosis in response to exposure to cytotoxic agents. Our results indicate that mitochondria/mitochondrial DNA play a direct role in modulating aspects of the tumorigenic phenotype, although they are not necessarily a sine qua non for apoptotic cell death. This is particularly interesting because most tumor tissues are more dependent upon glycolysis for energy production, rather than mitochondrially mediated oxidative phosphorylation. Creation of rho(-) cells will be useful to study the mitochondrial processes involved in tumorigenesis.
Cavalli
L R
LR
Department of Neurology, University of Colorado Health Sciences Center, Denver, USA.
Varella-Garcia
M
M
Liang
B C
BC
D000818:Animals; D017209:Apoptosis; D002448:Cell Adhesion; D002471:Cell Transformation, Neoplastic; D004272:DNA, Mitochondrial / Q000502:physiology*; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000235:genetics*; D010641:Phenotype; D014407:Tumor Cells, Cultured
D004272:DNA, Mitochondrial