Novel role of androgens in mitochondrial fission and apoptosis.
Novel role of androgens in mitochondrial fission and apoptosis.
复制标题
DOI：
10.1158/1541-7786.mcr-10-0445
复制
发表时间：
2011-08
期刊：
影响因子：
--
通讯作者：
Kumar MV
中科院分区：
文献类型：
--
作者：
Choudhary V;Kaddour-Djebbar I;Lakshmikanthan V;Ghazaly T;Thangjam GS;Sreekumar A;Lewis RW;Mills IG;Bollag WB;Kumar MV
雄激素和雄激素受体（AR）通过靶基因的转录调节在前列腺癌的增殖中起关键作用。在这里，我们发现，雄激素上调动力蛋白相关蛋白1（Drp 1）的表达，这是参与诱导线粒体分裂（MF），一个共同的事件在有丝分裂和凋亡。临床组织样本和各种前列腺癌细胞系显示Drp 1和AR水平之间呈正相关。用AR激动剂R1881和拮抗剂比卡鲁胺处理雄激素敏感细胞，表明Drp 1受雄激素的转录调控，这一点通过AR ChIP-seq测定得到证实。使用pAcGFP 1-Mito稳定转染的LNCaP（线粒体绿色）细胞的实时成像实验显示，雄激素本身不会诱导显著的MF，尽管Drp 1上调。然而，当用线粒体Ca 2+流出抑制剂CGP 37157（CGP）处理时，这些细胞表现出MF，这进一步增强了用R1881预处理，表明雄激素诱导的Drp 1促进了CGP诱导的MF。这种增强的MF与细胞凋亡增加相关。DN-Drp 1（K38 A）转染挽救了细胞凋亡增加，证实了雄激素诱导的Drp 1在联合治疗观察到的细胞凋亡中的作用。此外，我们发现CGP降低了Mfn 1的表达，Mfn 1是一种促进线粒体融合的蛋白质，这是一种对抗分裂的过程。我们认为，雄激素增加Drp 1增强MF导致细胞凋亡。目前的研究表明，雄激素在调节线粒体形态中的新作用，可能会被用于前列腺癌的治疗。
Androgen and androgen receptors (AR) play critical roles in the proliferation of prostate cancer through transcriptional regulation of target genes. Here, we found that androgens upregulated the expression of dynamin-related protein 1 (Drp1), which is involved in the induction of mitochondrial fission (MF), a common event in mitosis and apoptosis. Clinical tissue samples and various prostate cancer cell lines revealed a positive correlation between Drp1 and AR levels. Treatment of androgen-sensitive cells with an AR agonist, R1881, and antagonist, bicalutamide, showed that Drp1 is transcriptionally regulated by androgens, as confirmed by an AR ChIP-seq assay. Live imaging experiments using pAcGFP1-Mito stably transfected LNCaP (mito-green) cells revealed that androgen did not induce significant MF by itself, although Drp1 was upregulated. However, when treated with CGP37157 (CGP), an inhibitor of mitochondrial Ca2+ efflux, these cells exhibited MF, which was further enhanced by pre-treatment with R1881, suggesting that androgen-induced Drp1 facilitated CGP-induced MF. This enhanced MF was correlated with increased apoptosis. Transfection with DN-Drp1 (K38A) rescued cells from increased apoptosis, confirming the role of androgen-induced Drp1 in the observed apoptosis with combination treatment. Further, we found that CGP reduced the expression of Mfn1, a protein that promotes mitochondrial fusion, a process which opposes fission. We suggest that androgen-increased Drp1 enhanced MF leading to apoptosis. The present study demonstrates a novel role for androgens in the regulation of mitochondrial morphology that could potentially be utilized in prostate cancer therapy.