Betulinic acid suppresses constitutive and TNFalpha-induced NF-kappaB activation and induces apoptosis in human prostate carcinoma PC-3 cells.
Betulinic acid suppresses constitutive and TNFalpha-induced NF-kappaB activation and induces apoptosis in human prostate carcinoma PC-3 cells.
复制标题
DOI：
10.1002/mc.20447
复制
发表时间：
2008-12
影响因子：
4.6
通讯作者：
Gupta, Sanjay
中科院分区：
文献类型：
--
作者：
Rabi, Thangaiyan;Shukla, Sanjeev;Gupta, Sanjay
雄激素难治性前列腺癌细胞中化学耐药性的发展部分是由于调节多种细胞存活和抗凋亡基因的 Rel/NF-κB 转录因子的组成型激活。在这项研究中，我们检查了桦木酸 (BetA)（一种来自白桦树皮的五环三萜）是否能有效抑制表现出高组成型 NF-κB 表达的雄激素难治性人前列腺癌细胞中的 NF-κB 表达。用 BetA 处理 PC-3 细胞可抑制 DNA 结合并降低 NF-κB/p65 的核水平。 BetA 介导的 NF-κB 抑制涉及降低 IKK 活性以及 IκBα 在丝氨酸 32/36 处的磷酸化，随后发生降解。报告基因检测显示 BetA 抑制 NF-κB 具有转录活性。研究发现这些效应与 Bax/Bcl-2 比率的变化以及聚 (ADP) 核糖聚合酶的裂解更倾向于细胞凋亡相关。 BetA 还通过 IκBα 途径抑制 TNFα 诱导的 NF-κB 激活，从而使细胞对 TNFα 诱导的细胞凋亡敏感。我们的研究表明，BetA 能有效抑制 NF-κB 的组成性激活，并支持通过与 BetA 联合治疗雄激素难治性前列腺癌来靶向 NF-κB 的基本原理。
Development of chemoresistance in androgen-refractory prostate cancer cells is partly due to constitutive activation of Rel/NF-κB transcription factors that regulate several cell survival and anti-apoptotic genes. In this study we examined whether betulinic acid (BetA), a pentacyclic triterpene from the bark of white birch, is effective in inhibiting NF-κB expression in androgen-refractory human prostate cancer cells exhibiting high constitutive NF-κB expression. Treatment of PC-3 cells with BetA inhibited DNA binding and reduced nuclear levels of the NF-κB/p65. BetA-mediated NF-κB inhibition involved decreased IKK activity and phosphorylation of IκBα at serine 32/36 followed by its degradation. Reporter assays revealed that NF-κB inhibition by BetA is transcriptionally active. These effects were found to correlate with a shift in Bax/Bcl-2 ratio and cleavage of poly(ADP)ribose polymerase more towards apoptosis. BetA also inhibited TNFα-induced activation of NF-κB via the IκBα pathway, thereby sensitizing the cells to TNFα-induced apoptosis. Our studies demonstrate that BetA effectively inhibits constitutive NF-κB activation and supports the rationale for targeting NF-κB through combination protocols with BetA in androgen-refractory prostate cancer.
登录
查看更多内容
影响因子：
4
作者：
Lindholm, PF;Bub, J;Kajdacsy-Balla, A
通讯作者：
Kajdacsy-Balla, A
影响因子：
6.5
作者：
Selzer, E;Pimentel, E;Kodym, R
通讯作者：
Kodym, R
影响因子：
4.8
作者：
Fulda, S;Debatin, KM
通讯作者：
Debatin, KM
影响因子：
3.7
作者：
Meng, RD;El-Deiry, WS
通讯作者：
El-Deiry, WS
DOI：
10.1073/pnas.91.9.3564
发表时间：
1994-04-26
影响因子：
11.1
作者：
MAYAUX, JF;BOUSSEAU, A;LEPECQ, JB
通讯作者：
LEPECQ, JB