Mitochondrial DNA determines androgen dependence in prostate cancer cell lines
Mitochondrial DNA determines androgen dependence in prostate cancer cell lines
复制标题
DOI：
10.1038/sj.onc.1209190
复制
发表时间：
2006-03-01
期刊：
影响因子：
8
通讯作者：
Gotoh, A
中科院分区：
文献类型：
--
作者：
Higuchi, M;Kudo, T;Gotoh, A
前列腺癌在雄激素消融治疗后从雄激素依赖性发展到雄激素非依赖性阶段。线粒体DNA在细胞死亡和转移能力中起作用。此外，异质性大缺失线粒体DNA在前列腺癌中非常常见。为了探讨线粒体DNA在前列腺癌雄激素依赖性中的作用，我们测试了正常和缺失的线粒体DNA随前列腺癌进展的变化。我们证明，雄激素非依赖性细胞系C4-2，建立了雄激素依赖性LNCaP细胞系接种到去势小鼠，有一个大大减少的正常线粒体DNA的量和大缺失DNA的积累。引人注目的是，从雄激素依赖性LNCaP的线粒体DNA的耗尽导致雄激素依赖性的丧失。正常线粒体DNA重建线粒体DNA耗尽的克隆恢复雄激素依赖。这些结果表明，线粒体DNA决定前列腺癌细胞系的雄激素依赖性。此外，线粒体DNA缺陷细胞在去势无胸腺小鼠中形成肿瘤，而LNCaP没有。因此，线粒体DNA的大量缺失和消耗的积累可能在雄激素非依赖性的发展中发挥作用，导致前列腺癌的进展。
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.