Combination of curcumin and bicalutamide enhanced the growth inhibition of androgen-independent prostate cancer cells through SAPK/JNK and MEK/ERK1/2-mediated targeting NF-κB/p65 and MUC1-C.
Combination of curcumin and bicalutamide enhanced the growth inhibition of androgen-independent prostate cancer cells through SAPK/JNK and MEK/ERK1/2-mediated targeting NF-κB/p65 and MUC1-C.
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DOI：
10.1186/s13046-015-0168-z
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发表时间：
2015-05-15
期刊：
影响因子：
--
通讯作者：
Hann SS
中科院分区：
文献类型：
--
作者：
Li J;Xiang S;Zhang Q;Wu J;Tang Q;Zhou J;Yang L;Chen Z;Hann SS
前列腺癌是男性最常见的恶性肿瘤之一。粘蛋白1（MUC 1）异二聚体癌蛋白在具有侵袭性病理和临床特征的人前列腺癌中过表达，导致预后不良。然而，MUC 1 C-末端结构域（MUC 1-C）在雄激素非依赖性前列腺癌发生和发展中的功能作用仍不清楚。通过MTT测定法测量细胞活力。Western blot检测SAPK/JNK、ERK 1/2、MUC 1-C、NF-κB亚基p65和p50的磷酸化和蛋白表达。瞬时转染法和电穿孔转染法检测MUC 1-C、NF-κB亚单位p65的外源性表达。我们发现姜黄素抑制雄激素非依赖性前列腺癌细胞的生长，并且在姜黄素和雄激素受体拮抗剂比卡鲁胺的存在下观察到协同作用。为了进一步探索潜在的机制，我们发现姜黄素增加了ERK 1/2和SAPK/JNK的磷酸化，比卡鲁胺增强了这一点。此外，姜黄素还能降低MUC 1-C和NF-κB亚基p65的蛋白表达，而MEK/ERK 1/2（PD 98059）和SAPK/JNK（SP 60015）抑制剂可使其消失。在姜黄素与比卡鲁胺的组合中观察到进一步降低。此外，虽然外源性表达MUC 1-C对姜黄素减少的p65几乎没有影响，但p65的过表达逆转了姜黄素对MUC 1-C蛋白表达的影响，表明p65位于MUC 1-C的上游。有趣的是，我们发现MUC 1-C反馈的外源性表达减弱了姜黄素对ERK 1/2和SAPK/JNK磷酸化的影响，并拮抗了姜黄素对细胞生长的影响。我们的研究结果表明，姜黄素抑制雄激素非依赖性前列腺癌细胞的生长，通过ERK 1/2和SAPK/JNK介导的抑制p65，其次是减少MUC 1-C蛋白的表达。更重要的是，姜黄素和比卡鲁胺具有协同作用。MUC 1-C对ERK 1/2和SAPK/JNK的负反馈调节环进一步证明了MUC 1-C对姜黄素的整体反应的作用。本研究揭示了姜黄素与比卡鲁胺联合应用增强雄激素非依赖性前列腺癌细胞生长抑制的潜在分子机制。
Prostate cancer is one of the most common malignancies in men. The mucin 1 (MUC1) heterodimeric oncoprotein is overexpressed in human prostate cancers with aggressive pathologic and clinical features, resulting in a poor outcome. However, the functional role for MUC1 C-terminal domain (MUC1-C) in androgen-independent prostate cancer occurrence and development has remained unclear. Cell viability was measured by MTT assays. Western blot analysis was performed to measure the phosphorylation and protein expression of SAPK/JNK and ERK1/2, and MUC1-C, NF-κB subunit p65 and p50. Exogenous expression of MUC1-C, NF-κB subunit p65 was carried out by transient and electroporated transfection assays. We showed that curcumin inhibited the growth of androgen-independent prostate cancer cells and a synergy was observed in the presence of curcumin and bicalutamide, the androgen receptor antagonist. To further explore the potential mechanism underlining this, we found that curcumin increased the phosphorylation of ERK1/2 and SAPK/JNK, which was enhanced by bicalutamide. In addition, curcumin reduced the protein expression of MUC1-C and NF-κB subunit p65, which were abrogated in the presence of the inhibitors of MEK/ERK1/2 (PD98059) and SAPK/JNK (SP60015). A further reduction was observed in the combination of curcumin with bicalutamide. Moreover, while exogenous expression of MUC1-C had little effect on curcumin-reduced p65, the overexpression of p65 reversed the effect of curcumin on MUC1-C protein expression suggesting that p65 is upstream of MUC1-C. Intriguingly, we showed that exogenous expression of MUC1-C feedback diminished the effect of curcumin on phosphorylation of ERK1/2 and SAPK/JNK, and antagonized the effect of curcumin on cell growth. Our results show that curcumin inhibits the growth of androgen-independent prostate cancer cells through ERK1/2- and SAPK/JNK-mediated inhibition of p65, followed by reducing expression of MUC1-C protein. More importantly, there are synergistic effects of curcumin and bicalutamide. The negative feedback regulatory loop of MUC1-C to ERK1/2 and SAPK/JNK further demonstrates the role of MUC1-C that contributes to the overall responses of curcumin. This study unveils the potential molecular mechanism by which combination of curcumin with bicalutamide enhances the growth inhibition of androgen-independent prostate cancer cells.
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