PMS1077抑制NF-кB活化并促进TNF-α诱导的前列腺癌细胞凋亡
摘要
核因子kappa B (NF-κB)是普遍存在于哺乳动物中的转录因子,其参与多种恶性肿瘤相关基因的表达调控。NF-κB在细胞增殖、抵抗凋亡、细胞迁移、血管新生等癌症发生发展过程中发挥关键作用,因此NF-κB信号通路已成为多种恶性肿瘤治疗和药物发现的一个重要靶点。PMS化合物是一系列同时具有抗血小板激活因子活性和抗HIV-1病毒活性的哌嗪类衍生物,本研究组前期研究证明其中PMS1077能够诱导B淋巴瘤Raji细胞的凋亡和急性早幼粒白血病HL-60细胞的再分化,但其作用机理尚不明确。
本研究旨在以NF-κB信号通路为靶点探讨PMS化合物的抗肿瘤活性及其作用机理。首先在稳定表达NF-κB调控荧光素酶报告基因的前列腺癌细胞DU145和PC3中初步评价了11种PMS同系物对NF-κB活性的影响,其中PMS1077、PMS1120和PMS1144能够显著抑制肿瘤坏死因子(TNF-α)诱导的NF-κB信号通路活性,同时MTT实验证明此三种PMS化合物具有较低的细胞毒性作用；采用双荧光素酶报告基因系统进一步准确评价了PMS1077对NF-κB活性的影响,发现PMS1077(20、40、60和80μM)对NF-κB活性的抑制呈现浓度依赖效应；免疫印迹实验结果显示PMS1077能够抑制TNF-α诱导的NF-κB抑制蛋白(IKB-α)的磷酸化和降解以及NF-κB异源二聚体中p65的磷酸化；免疫细胞化学和细胞核质分离实验结果证明PMS1077抑制了TNF-α诱导p65的核转位；通过计算机分子动力学模拟对接手段推测PMS1077可能是通过直接结合IKK-β (IκB激酶p)亚基的激酶结构域从而抑制了后续信号通路的活化；MTT细胞增殖与流式细胞凋亡分析发现PMS1077能够显著促进TNF-α诱导的前列腺癌细胞凋亡；免疫印迹和RT-PCR对基因表达分析表明PMS1077处理细胞显著下调了NF-κB调控抗凋亡基因Bcl-xL、Bcl-2和Survivin的表达,同时促进了TNF-α诱导凋亡特征性蛋白分子PARP的裂解。
综上所述,PMS1077可以通过下调前列腺癌细胞中NF-κB调控的抗凋亡基因表达而促进TNF-α诱导的细胞凋亡效应。本研究工作部分阐述了PMS化合物抗肿瘤活性的作用机理,为进一步优化该系列化合物的结构和改善其抗肿瘤生物活性提供了理论依据。
The nuclear factor-kappa B (NF-κB) are ubiquitous eukaryotic transcription factors in mammals that regulate key genes involved in the development of numerous malignant tumors. Because of its critical role in tumor cell survival, proliferation, invasion, metastasis, and angiogenesis, NF-κB signaling pathway has become a key therapeutic target for anti-caner drug development. PMS compounds are tri-substituted derivatives of piperazine with anti-PAF and anti-HIV-1properties. Our previous studies have demonstrated that PMS1077could induce apoptosis of Raji cells and differentiation of HL-60cells, but the mechanism of action remains unclear.
In this study, we mainly focus on the mechanisms involved in the anti-cancer activities of PMS compounds by evaluating their effects on NF-κB signaling pathway. We first determined the effects of11PMS structural analogs on NF-κB signaling acticity in DU145and PC3cell lines stably expressing a NF-κB promoter driving luciferase reporter. We found that PMS1077, PMS1120, and PMS1144significantly inhibited TNF-a induced NF-κB activity and showed a moderate cytotoxicity in MTT assay. In the further more accurate dual-luciferase assay, PMS1077(20,40,60, and80μM) was found to inhibit the TNF-a induced NF-κB activity in a dose dependent manner. Western blot assay indicated that PMS1077suppressed the TNF-a induced inhibitor of κB alpha (IκB-α) phosphorylation, IκB-a degradation, and p65phosphorylation. PMS1077consistently blocked TNF-a induced p65nuclear translocation as demonstrated in the immunocytochemistry and Western blot assay used. Molecular docking studies predicted that PMS1077might suppress the activation of NF-κB by interacting directly with the IκB kinase-P (IKK-P) subunit. In addition, we further found that PMS1077significantly sensitized DU145cells to TNF-a induced apoptosis, as evidenced by MTT assay and flow cytometry. Results from Western blot and RT-PCR assay showed that TNF-a induced expression of the anti-apoptosis genes Bcl-xL, Bcl-2, and Survivin were down-regulated and TNF-a induced cleavage of PARP was significantly increased by PMS1077.
Finally, the present study demonstrated that PMS1077sensitized prostate cancer cells to TNF-a induced apoptosis by suppressing the expression of NF-κB regulated anti-apoptotic genes.Accordingly, the present data partially explained the mechanism underlying the anti-tumor activities of PMS compounds and may help us to further optimize their structures and improve their properties for potential anti-cancer drug development.
本研究旨在以NF-κB信号通路为靶点探讨PMS化合物的抗肿瘤活性及其作用机理。首先在稳定表达NF-κB调控荧光素酶报告基因的前列腺癌细胞DU145和PC3中初步评价了11种PMS同系物对NF-κB活性的影响,其中PMS1077、PMS1120和PMS1144能够显著抑制肿瘤坏死因子(TNF-α)诱导的NF-κB信号通路活性,同时MTT实验证明此三种PMS化合物具有较低的细胞毒性作用；采用双荧光素酶报告基因系统进一步准确评价了PMS1077对NF-κB活性的影响,发现PMS1077(20、40、60和80μM)对NF-κB活性的抑制呈现浓度依赖效应；免疫印迹实验结果显示PMS1077能够抑制TNF-α诱导的NF-κB抑制蛋白(IKB-α)的磷酸化和降解以及NF-κB异源二聚体中p65的磷酸化；免疫细胞化学和细胞核质分离实验结果证明PMS1077抑制了TNF-α诱导p65的核转位；通过计算机分子动力学模拟对接手段推测PMS1077可能是通过直接结合IKK-β (IκB激酶p)亚基的激酶结构域从而抑制了后续信号通路的活化；MTT细胞增殖与流式细胞凋亡分析发现PMS1077能够显著促进TNF-α诱导的前列腺癌细胞凋亡；免疫印迹和RT-PCR对基因表达分析表明PMS1077处理细胞显著下调了NF-κB调控抗凋亡基因Bcl-xL、Bcl-2和Survivin的表达,同时促进了TNF-α诱导凋亡特征性蛋白分子PARP的裂解。
综上所述,PMS1077可以通过下调前列腺癌细胞中NF-κB调控的抗凋亡基因表达而促进TNF-α诱导的细胞凋亡效应。本研究工作部分阐述了PMS化合物抗肿瘤活性的作用机理,为进一步优化该系列化合物的结构和改善其抗肿瘤生物活性提供了理论依据。
The nuclear factor-kappa B (NF-κB) are ubiquitous eukaryotic transcription factors in mammals that regulate key genes involved in the development of numerous malignant tumors. Because of its critical role in tumor cell survival, proliferation, invasion, metastasis, and angiogenesis, NF-κB signaling pathway has become a key therapeutic target for anti-caner drug development. PMS compounds are tri-substituted derivatives of piperazine with anti-PAF and anti-HIV-1properties. Our previous studies have demonstrated that PMS1077could induce apoptosis of Raji cells and differentiation of HL-60cells, but the mechanism of action remains unclear.
In this study, we mainly focus on the mechanisms involved in the anti-cancer activities of PMS compounds by evaluating their effects on NF-κB signaling pathway. We first determined the effects of11PMS structural analogs on NF-κB signaling acticity in DU145and PC3cell lines stably expressing a NF-κB promoter driving luciferase reporter. We found that PMS1077, PMS1120, and PMS1144significantly inhibited TNF-a induced NF-κB activity and showed a moderate cytotoxicity in MTT assay. In the further more accurate dual-luciferase assay, PMS1077(20,40,60, and80μM) was found to inhibit the TNF-a induced NF-κB activity in a dose dependent manner. Western blot assay indicated that PMS1077suppressed the TNF-a induced inhibitor of κB alpha (IκB-α) phosphorylation, IκB-a degradation, and p65phosphorylation. PMS1077consistently blocked TNF-a induced p65nuclear translocation as demonstrated in the immunocytochemistry and Western blot assay used. Molecular docking studies predicted that PMS1077might suppress the activation of NF-κB by interacting directly with the IκB kinase-P (IKK-P) subunit. In addition, we further found that PMS1077significantly sensitized DU145cells to TNF-a induced apoptosis, as evidenced by MTT assay and flow cytometry. Results from Western blot and RT-PCR assay showed that TNF-a induced expression of the anti-apoptosis genes Bcl-xL, Bcl-2, and Survivin were down-regulated and TNF-a induced cleavage of PARP was significantly increased by PMS1077.
Finally, the present study demonstrated that PMS1077sensitized prostate cancer cells to TNF-a induced apoptosis by suppressing the expression of NF-κB regulated anti-apoptotic genes.Accordingly, the present data partially explained the mechanism underlying the anti-tumor activities of PMS compounds and may help us to further optimize their structures and improve their properties for potential anti-cancer drug development.
引文
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