Silibinin inhibits constitutive activation of Stat3, and causes caspase activation and apoptotic death of human prostate carcinoma DU145 cells
Silibinin inhibits constitutive activation of Stat3, and causes caspase activation and apoptotic death of human prostate carcinoma DU145 cells
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DOI：
10.1093/carcin/bgm042
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发表时间：
2007-07-01
期刊：
影响因子：
4.7
通讯作者：
Agarwal, Rajesh
中科院分区：
文献类型：
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作者：
Agarwal, Chapla;Tyagi, Alpna;Agarwal, Rajesh
转录因子信号转导子和转录激活子（Stat）-3在前列腺癌（PCA）中被组成性激活，这表明其破坏可能是控制这种恶性肿瘤的有效方法。在这里，我们评估了水飞蓟宾（Silybum marianum中的一种黄烷酮，在各种癌症模型中具有已证实的抗癌功效）是否抑制DU 145细胞中的Stat 3激活，如果确实如此，细胞的生物学命运是什么？在50 μ M或更高浓度下持续24或48小时，在血清和血清饥饿条件下，水飞蓟宾浓度依赖性地降低了组成性Stat 3在Tyr 705和Ser 727残基处的磷酸化。组成性活性Stat 3-DNA结合也被Silibinin浓度依赖性地抑制;然而，仅在血清饥饿条件下，Silibinin才观察到细胞凋亡死亡以及半胱天冬酶和聚（ADP-核糖）聚合酶（PARP）切割，这表明在血清条件下还有其他生存途径活跃。在其他研究中，用各种特定的药理学抑制剂处理细胞，其中表皮生长因子受体和促分裂原活化蛋白/细胞外信号调节激酶激酶（MEK 1/2）抑制剂不降低Stat 3的磷酸化，表明这些抑制剂在DU 145细胞中Stat 3活化中缺乏显著作用。Janus激酶（JAK）-1和JAK 2抑制剂强烈降低Stat 3磷酸化，但不导致凋亡性细胞死亡。有趣的是，JAK 1抑制剂仅与水飞蓟宾组合导致Stat 3在Tyr 705处磷酸化的完全减少，激活caspase-9和caspase-3，并引起DU 145细胞的强烈PARP切割和凋亡死亡。鉴于Stat 3激活在PCA中的关键作用，我们的研究结果表明，水飞蓟宾抑制组成性活性Stat 3并诱导DU 145细胞凋亡，因此可能在这种致命的恶性肿瘤的治疗干预中具有潜在的意义。
Transcription factor signal transducer and activator of transcription (Stat)-3 is activated constitutively in prostate cancer (PCA) suggesting that its disruption could be an effective approach to control this malignancy. Here we assessed whether silibinin, a flavanone from Silybum marianum with proven anticancer efficacy in various cancer models, inhibits Stat3 activation in DU145 cells, and if it does, what is the biological fate of the cells? At 50 mu M or higher concentrations for 24 or 48 h, silibinin concentration dependently reduced constitutive Stat3 phosphorylation at Tyr705 and Ser727 residues under both serum and serum-starved conditions. Constitutively active Stat3-DNA binding was also inhibited concentration dependently by silibinin; however, apoptotic death together with caspase and poly(ADP-ribose) polymerase (PARP) cleavage was observed by silibinin only under serum-starved conditions suggesting that additional survival pathways are active under serum conditions. In other studies, cells were treated with various specific pharmacological inhibitors where phosphorylation of Stat3 was not reduced by epidermal growth factor receptor and Mitogen activated protein/extracellular signal regulate kinase kinase (MEK1/2) inhibitors, suggesting lack of significant roles of these in Stat3 activation in DU145 cells. Janus kinase (JAK)-l and JAK2 inhibitors strongly reduced Stat3 phosphorylation but did not result in apoptotic cell death. Interestingly, JAK1 inhibitor only in combination with silibinin resulted in a complete reduction in Stat3 phosphorylation at Tyr705, activated caspase-9 and caspase-3, and caused strong PARP cleavage and apoptotic death of DU145 cells. Given a critical role of Stat3 activation in PCA, our results showed that silibinin inhibits constitutively active Stat3 and induces apoptosis in DU145 cells, and thus might have potential significance in therapeutic intervention of this deadly malignancy.