Down-regulation of androgen receptor by 3,3'-diindolylmethane contributes to inhibition of cell proliferation and induction of apoptosis in both hormone-sensitive LNCaP and insensitive C4-2B prostate cancer cells (Retracted article. See vol. 78, pg. 5473, 2018)
Down-regulation of androgen receptor by 3,3'-diindolylmethane contributes to inhibition of cell proliferation and induction of apoptosis in both hormone-sensitive LNCaP and insensitive C4-2B prostate cancer cells (Retracted article. See vol. 78, pg. 5473, 2018)
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DOI：
10.1158/0008-5472.can-06-2011
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发表时间：
2006-10-15
期刊：
影响因子：
11.2
通讯作者：
Sarkar, Fazlul H.
中科院分区：
文献类型：
--
作者：
Bhuiyan, Mohammad M. R.;Li, Yiwei;Sarkar, Fazlul H.
尽管雄激素剥夺治疗的初始疗效，大多数晚期前列腺癌患者最终进展为难治性前列腺癌，对此没有治愈性治疗。来自我们实验室和其他实验室的先前研究已经显示了3，3 '-二吲哚基甲烷（DIM）在前列腺癌细胞中的抗增殖和促凋亡作用。然而，DIM作用的分子机制尚未在雄激素受体（AR）阳性的前列腺癌细胞中进行研究。因此，我们研究了B-DIM（一种具有更高生物利用度的DIM制剂）对前列腺癌细胞中AR敏感的LNCaP（AR+）和对前列腺癌细胞不敏感的C4- 2 B（AR+）中AR、Akt和核因子κ B（NF-κ B）信号传导的影响。我们发现，B-DIM显着抑制细胞增殖，并诱导细胞凋亡，在这两个细胞系。通过Akt基因转染、逆转录-PCR、Western blot分析和电泳迁移率变动分析，我们发现Akt、NF-κ B B和AR之间存在潜在的串扰。重要的是，B-DIM显著抑制Akt活化、NF-κ B B DNA结合活性、AR磷酸化以及AR和前列腺特异性抗原的表达，表明B-DIM可以阻断串扰。共聚焦研究表明，B-DIM抑制AB核转位，导致AR靶基因的下调。此外，B-DIM显着抑制C4-2B细胞的生长在一个严重的联合免疫缺陷-实验性前列腺癌骨转移的人模型。这些结果表明，B-DIM诱导的细胞增殖抑制和凋亡诱导部分通过下调AR，Akt和NF-κ B信号转导介导。这些观察结果为设计新的治疗方法提供了理论基础，通过单独使用B-DIM或与其他治疗药物联合使用，治疗对前列腺癌敏感的前列腺癌，但更重要的是，治疗难治性前列腺癌。
Despite the initial efficacy of androgen deprivation therapy, most patients with advanced prostate cancer eventually progress to hormone-refractory prostate cancer, for which there is no curative therapy. Previous studies from our laboratory and others have shown the antiproliferative and proapoptotic effects of 3,3'-diindolylmethane (DIM) in prostate cancer cells. However, the molecular mechanism of action of DIM has not been investigated in androgen receptor (AR)-positive hormone-responsive and -nonresponsive prostate cancer cells. Therefore, we investigated the effects of B-DIM, a formulated DIM with greater bioavailability, on AR, Akt, and nuclear factor kappa B (NF-kappa B) signaling in hormone-sensitive LNCaP (AR+) and hormone-insensitive C4-2B (AR+) prostate cancer cells. We found that B-DIM significantly inhibited cell proliferation and induced apoptosis in both cell lines. By Akt gene transfection, reverse transcription-PCR, Western blot analysis, and electrophoretic mobility shift assay, we found a potential crosstalk between Akt, NF-kappa B, and AR. Importantly, B-DIM significantly inhibited Akt activation, NF-kappa B DNA binding activity, AR phosphorylation, and the expressions of AR and prostate-specific antigen, suggesting that B-DIM could interrupt the crosstalk. Confocal studies revealed that B-DIM inhibited AB nuclear translocation, leading to the down-regulation of AR target genes. Moreover, B-DIM significantly inhibited C4-2B cell growth in a severe combined immunodeficiency-human model of experimental prostate cancer bone metastasis. These results suggest that B-DIM-induced cell proliferation inhibition and apoptosis induction are partly mediated through the downregulation of AR, Akt, and NF-kappa B signaling. These observations provide a rationale for devising novel therapeutic approaches for the treatment of hormone-sensitive, but more importantly, hormone-refractory prostate cancer by using B-DIM alone or in combination with other therapeutics.