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Prostate cancer progresses from an androgen-dependent stage to androgen-independent after androgen ablation therapy. Mitochondrial DNA plays a role in cell death and metastatic competence. Further, heteroplasmic large deletion mitochondrial DNA is very common in prostate cancer. To investigate the role of mitochondrial DNA in androgen dependence of prostate cancers, we tested the changes of normal and deleted mitochondrial DNA in accordance with the progression of prostate cancer. We demonstrate that androgen-independent cell line C4-2, established by inoculation of androgen-dependent LNCaP into castrated mice, as compared with LNCaP, have 8 times reduced expression of normal mitochondrial DNA associated with an accumulation of large deletion. C4-2 has a marked decrease in respiratory function possibly due to the change of mitochondrial DNA. Strikingly, depletion of mitochondrial DNA from androgen-dependent LNCaP resulted in a loss of androgen dependence. Reconstitution of normal mitochondrial DNA to mitochondrial DNA-depleted clone restored androgen dependence. These results indicate that mitochondrial DNA determines androgen dependence of prostate cancer cell lines. Further, mitochondrial DNA-deficient cells formed tumors in castrated athymic mice, whereas LNCaP did not. The accumulation of large deletion and depletion of mitochondrial DNA may thus play a role in the development of androgen independence and progression of prostate cancers.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]