Guggulsterone inhibits NF-κB and IκBα kinase activation, suppresses expression of anti-apoptotic gene products, and enhances apoptosis
Guggulsterone inhibits NF-κB and IκBα kinase activation, suppresses expression of anti-apoptotic gene products, and enhances apoptosis
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DOI：
10.1074/jbc.m408093200
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发表时间：
2004-11-05
影响因子：
4.8
通讯作者：
Aggarwal, BB
中科院分区：
文献类型：
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作者：
Shishodia, S;Aggarwal, BB
Guggulsterone 源自没药 (Commiphora mukul)，用于治疗肥胖、糖尿病、高脂血症、动脉粥样硬化和骨关节炎，最近被证明可以拮抗法尼醇 X 受体并降低胆汁酸激活基因的表达。由于 NF-kappaB 的激活与古古甾酮影响的炎症性疾病密切相关，因此我们推测它必须调节 NF-kappaB 的激活。在本研究中，我们通过研究这种类固醇对炎症因子和致癌物诱导的 NF-κB 激活的影响来检验这一假设。 Guggulsterone 抑制由肿瘤坏死因子 (TNF)、佛波酯、冈田酸、香烟烟雾冷凝物、过氧化氢和白细胞介素 1 诱导的 NF-kappaB 的 DNA 结合。 NF-kappaB 激活不具有细胞类型特异性，因为上皮细胞和白血病细胞均受到抑制。 Guggulsterone 还抑制大多数肿瘤细胞中表达的 NF-kappaB 组成型激活。通过抑制 IkappaB 激酶激活，该类固醇阻断 IkappaBalpha 磷酸化和降解，从而抑制 p65 磷酸化和核转位。 TNF、TNFR1、TRADD、TRAF2、NIK 和 IKK 诱导的 NF-kappaB 依赖性报告基因转录也被 guggulsterone 阻断，但不影响 p65 介导的基因转录。此外，guggulsterone 降低了参与抗凋亡（IAP1、xIAP、Bfl-1/A1、Bcl-2、cFLIP 和 survivin）、增殖（cyclin D1 和 c-Myc）和转移（MMP-9、COX-2 和 VEGF）的基因产物的表达；这与 TNF 和化疗药物诱导的细胞凋亡增强有关。总体而言，我们的结果表明古古甾酮抑制 NF-kappaB 和 NF-kappaB 调节的基因产物，这可能解释了其抗炎活性。
Guggulsterone, derived from Commiphora mukul and used to treat obesity, diabetes, hyperlipidemia, atherosclerosis, and osteoarthritis, has been recently shown to antagonize the farnesoid X receptor and decrease the expression of bile acid-activated genes. Because activation of NF-kappaB has been closely linked with inflammatory diseases affected by guggulsterone, we postulated that it must modulate NF-kappaB activation. In the present study, we tested this hypothesis by investigating the effect of this steroid on the activation of NF-kappaB induced by inflammatory agents and carcinogens. Guggulsterone suppressed DNA binding of NF-kappaB induced by tumor necrosis factor (TNF), phorbol ester, okadaic acid, cigarette smoke condensate, hydrogen peroxide, and interleukin-1. NF-kappaB activation was not cell type-specific, because both epithelial and leukemia cells were inhibited. Guggulsterone also suppressed constitutive NF-kappaB activation expressed in most tumor cells. Through inhibition of IkappaB kinase activation, this steroid blocked IkappaBalpha phosphorylation and degradation, thus suppressing p65 phosphorylation and nuclear translocation. NF-kappaB-dependent reporter gene transcription induced by TNF, TNFR1, TRADD, TRAF2, NIK, and IKK was also blocked by guggulsterone but without affecting p65-mediated gene transcription. In addition, guggulsterone decreased the expression of gene products involved in anti-apoptosis (IAP1, xIAP, Bfl-1/A1, Bcl-2, cFLIP, and survivin), proliferation ( cyclin D1 and c-Myc), and metastasis (MMP-9, COX-2, and VEGF); this correlated with enhancement of apoptosis induced by TNF and chemotherapeutic agents. Overall, our results indicate that guggulsterone suppresses NF-kappaB and NF-kappaB-regulated gene products, which may explain its anti-inflammatory activities.