Niclosamide suppresses cell migration and invasion in enzalutamide resistant prostate cancer cells via Stat3-AR axis inhibition.
Niclosamide suppresses cell migration and invasion in enzalutamide resistant prostate cancer cells via Stat3-AR axis inhibition.
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DOI：
10.1002/pros.23015
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发表时间：
2015-09
期刊：
影响因子：
--
通讯作者：
Gao AC
中科院分区：
文献类型：
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作者：
Liu C;Lou W;Armstrong C;Zhu Y;Evans CP;Gao AC
众所周知，前列腺癌细胞中IL6的过度表达赋予了恩杂鲁胺耐药性，这可能是通过组成型Stat3激活发生的。此外，最近的临床前研究表明，enzalutamide可能具有通过Stat3激活诱导前列腺癌细胞转移的潜在不良作用。本研究旨在靶向Stat3激活并改善enzalutamide治疗。前列腺癌细胞对恩杂鲁胺的敏感性采用细胞生长试验和克隆生成试验。进行伤口愈合和侵袭试验，以确定细胞在体外的迁移和侵袭。采用定量逆转录pcr、elisa和Western blotting检测PSA、c-Myc、survivin、Stat3和AR的表达水平，ChIP检测AR对PSA启动子的募集情况。在本研究中，我们发现奈洛沙胺，一种先前发现的雄激素受体变异（AR-V7）的新型抑制剂，抑制Stat3磷酸化和下游靶基因的表达。硝氯沙胺可协同逆转前列腺癌细胞对恩杂鲁胺的耐药性，硝氯沙胺与恩杂鲁胺联合治疗可显著诱导细胞凋亡，抑制细胞生长、集落形成、细胞迁移和侵袭。Stat3的下调消除了恩杂鲁胺耐药性，导致表达IL6的前列腺癌细胞中AR对PSA启动子的募集减少。此外，氯硝柳胺通过下调Stat3靶基因表达Stat3和取消AR对PSA启动子的募集导致PSA抑制来逆转enzalutamide耐药。本研究表明前列腺癌中的IL6-Stat3-AR轴是恩杂鲁胺耐药的重要机制之一。奈洛沙胺有潜力靶向IL6-Stat3-AR通路，克服恩杂鲁胺耐药，抑制晚期前列腺癌的迁移和侵袭。
It is known that over expression of IL6 in prostate cancer cells confer enzalutamide resistance and that this may occur through constitutive Stat3 activation. Additionally, recent pre-clinical studies suggested enzalutamide might have the potential adverse effect of inducing metastasis of prostate cancer cells via Stat3 activation. This study is aimed to target Stat3 activation and improve enzalutamide therapy. Sensitivity of prostate cancer cells to enzalutamide was tested using cell growth assays and clonogenic assays. Wound healing and invasion assays were performed to determine cell migration and invasion in vitro. Quantitative reverse transcription-PCR, ELISAand Western blotting were performed to detect expression levels of PSA, c-Myc, survivin, Stat3 and AR. ChIP assay was performed to examine recruitment of AR to the PSA promoter. In the present study, we found niclosamide, a previously identified novel inhibitor of androgen receptor variant (AR-V7), inhibited Stat3 phosphorylation and expression of downstream target genes. Niclosamide synergistically reversed enzalutamide resistance in prostate cancer cells and combination treatment of niclosamide with enzalutamide significantly induced cell apoptosis and inhibited cell growth, colony formation, cell migration and invasion. Knock down of Stat3 abrogated enzalutamide resistance resulting in reduced recruitment of AR to the PSA promoter in prostate cancer cells expressing IL6. Moreover, niclosamide reversed enzalutamide resistance by down-regulating Stat3 target gene expression Stat3and abrogating recruitment of AR to PSA promoter resulting in PSA inhibition. This study demonstrated the IL6-Stat3-AR axis in prostate cancer is one of the crucial mechanisms of enzalutamide resistance. Niclosamide has the potential to target the IL6-Stat3-AR pathway to overcome enzalutamide resistance and inhibit migration and invasion in advanced prostate cancer.