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Mitochondrial DNA determines androgen dependence in prostate cancer cell lines

Oncogene volume 25, pages 1437–1445 (2006)Cite this article

Abstract

Prostate cancer progresses from an androgen-dependent to androgen-independent stage 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 demonstrated that the androgen-independent cell line C4-2, established by inoculation of the androgen-dependent LNCaP cell line into castrated mice, has a greatly reduced amount of normal mitochondrial DNA and an accumulation of large-deletion DNA. Strikingly, the depletion of mitochondrial DNA from androgen-dependent LNCaP resulted in a loss of androgen dependence. Reconstitution of normal mitochondrial DNA to the 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, leading to progression of prostate cancers.

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Acknowledgements

We thank Drs Tetsuo Ashizawa and Gordon B Mills for careful review of the manuscript. We thank Dr Yasuhisa Nakayama for his help in establishing long range PCR. We thank Dr Yutaka Nishigaki for his help in establishing Southern blotting. This work was supported by Charlotte Geyer Foundation, Taiho Pharmaceutical Co., Ltd, Tobacco Settlement at State of Arkansas and NIH grant RO1 CA100846 to M Higuchi.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR, USA

    M Higuchi, T Kudo, S Suzuki & T T Evans

  2. VA Medical Center and Department of Neurology, Houston, TX, USA

    M Higuchi & R Sasaki

  3. Baylor College of Medicine, Houston, TX, USA

    M Higuchi

  4. Department of Radiology, Kobe University School of Medicine, Chuo-ku, Kobe, Japan

    R Sasaki

  5. Department of Clinical Genetics, Kobe University School of Medicine, Chuo-ku, Kobe, Japan

    Y Wada, T Shirakawa & A Gotoh

  6. Department of Urology, Kobe University School of Medicine, Chuo-ku, Kobe, Japan

    T Shirakawa & A Gotoh

  7. International Center for Medical Research, Kobe University School of Medicine, Chuo-ku, Kobe, Japan

    T Shirakawa & A Gotoh

  8. Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR, USA

    J R Sawyer

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  1. M Higuchi
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Correspondence to M Higuchi.

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Higuchi, M., Kudo, T., Suzuki, S. et al. Mitochondrial DNA determines androgen dependence in prostate cancer cell lines. Oncogene 25, 1437–1445 (2006). https://doi.org/10.1038/sj.onc.1209190

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