Triptolide, histone acetyltransferase inhibitor, suppresses growth and chemosensitizes leukemic cells through inhibition of gene expression regulated by TNF-TNFR1-TRADD-TRAF2-NIK-TAK1-IKK pathway.
Triptolide, histone acetyltransferase inhibitor, suppresses growth and chemosensitizes leukemic cells through inhibition of gene expression regulated by TNF-TNFR1-TRADD-TRAF2-NIK-TAK1-IKK pathway.
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DOI：
10.1016/j.bcp.2011.07.062
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发表时间：
2011-11-01
影响因子：
5.8
通讯作者：
Aggarwal, Bharat B.
中科院分区：
文献类型：
--
作者：
Park, Byoungduck;Sung, Bokyung;Yadav, Vivek R.;Chaturvedi, Madan M.;Aggarwal, Bharat B.
雷公藤甲素是中草药雷公藤中的一种二萜三环氧化物，其抗炎和免疫抑制作用是通过抑制转录因子核因子-κB(NF-κB)途径实现的，其作用机制尚不完全清楚。我们发现，在纳摩尔浓度下，雷公藤甲素抑制了原生性和诱导性的NF-κB的激活，但不直接抑制p65与DNA的结合。二萜可阻断肿瘤坏死因子诱导的泛素化、磷酸化和IκBα的降解，并通过抑制p65与κ/p300的结合而抑制p65的乙酰化。雷公藤甲素还抑制I-κB-α激酶(IKK)，后者激活核因子-κB和丝氨酸276536处p65的磷酸化。此外，三环氧化物可完全消除TRAF2-TRAF2-NIK-κ-IKKβ诱导的NF-TRAFB报告活性。雷公藤内酯醇还可抑制肿瘤坏死因子诱导的细胞存活蛋白(XIAP、BclXL、Bcl2、Survivin、CIAP-1和CIAP-2)、细胞增殖蛋白(Cyclin D1、c-myc和环氧合酶-2)和转移蛋白(ICAM-1和MMP9)的表达。这导致了肿瘤坏死因子、紫杉醇和沙利度胺诱导的细胞凋亡被二萜类化合物增强，并抑制了肿瘤的侵袭。总之，我们的结果表明，雷公藤内酯醇可以阻断由肿瘤坏死因子-肿瘤坏死因子受体-TRADD-TRAF2-NIK-TAK1-IKK激活的炎症通路，增强细胞对凋亡的敏感性，并抑制肿瘤细胞的侵袭。
Triptolide, a diterpene triepoxide, from the Chinese herb Tripterygium wilfordii Hook.f, exerts its anti-inflammatory and immunosuppressive activities by inhibiting the transcription factor nuclear factor-κB (NF-κB) pathway, through a mechanism not yet fully understood. We found that triptolide, in nanomolar concentrations, suppressed both constitutive and inducible NF-κB activation, but did not directly inhibit binding of p65 to the DNA. The diterpene did block TNF-induced ubiquitination, phosphorylation, and degradation of IκBα, the inhibitor of NF-κB and inhibited acetylation of p65 through suppression of binding of p65 to CBP/p300. Triptolide also inhibited the IκBα kinase (IKK) that activates NF-κB and phosphorylation of p65 at serine 276, 536. Furthermore, the NF-κB reporter activity induced by TNF-TNFR1-TRADD-TRAF2- NIK-TAK1-IKKβ was abolished by the triepoxide. Triptolide also abrogated TNF-induced expression of cell survival proteins (XIAP, Bcl-xL, Bcl-2, survivin, cIAP-1 and cIAP-2), cell proliferative proteins (cyclin D1, c-myc and cyclooxygenase-2), and metastasis proteins (ICAM-1 and MMP-9). This led to enhancement of apoptosis induced by TNF, taxol, and thalidomide by the diterpene and to suppression of tumor invasion. Overall, our results demonstrate that triptolide can block the inflammatory pathway activated by TNF-TNFR1-TRADD-TRAF2-NIK-TAK1-IKK, sensitizes cells to apoptosis, and inhibits invasion of tumor cells.
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DOI：
10.1007/bf00124213
发表时间：
1982-01-01
期刊：
Cancer metastasis reviews
影响因子：
--
作者：
Liotta, L A;Thorgeirsson, U P;Garbisa, S
通讯作者：
Garbisa, S
影响因子：
3.6
作者：
Liu, Qiuyan;Chen, Taoyong;Cao, Xuetao
通讯作者：
Cao, Xuetao
影响因子：
4
作者：
Aggarwal, Bharat B.;Sethi, Gautam;Shishodia, Shishir
通讯作者：
Shishodia, Shishir
影响因子：
16
作者：
Campbell, KJ;Rocha, S;Perkins, ND
通讯作者：
Perkins, ND
影响因子：
20.3
作者：
Carter, Bing Z.;Mak, Duncan H.;Andreeff, Michael
通讯作者：
Andreeff, Michael