Retigeric acid B exhibits antitumor activity through suppression of nuclear factor-κB signaling in prostate cancer cells in vitro and in vivo.
Retigeric acid B exhibits antitumor activity through suppression of nuclear factor-κB signaling in prostate cancer cells in vitro and in vivo.
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DOI：
10.1371/journal.pone.0038000
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Lou HX
中科院分区：
文献类型：
--
作者：
Liu YQ;Hu XY;Lu T;Cheng YN;Young CY;Yuan HQ;Lou HX
以前，我们报道了瑞替格酸B（RB），一种从地衣中分离的天然五环三萜酸，抑制雄激素非依赖性前列腺癌（PCa）细胞的生长并诱导凋亡。然而，RB的作用机制仍不清楚。本研究以PC 3和DU 145细胞为模型，发现RB可抑制IκBα和NF-κB p65亚基的磷酸化水平，并呈时间和剂量依赖性。进一步研究发现，RB可抑制p65的核转位及其DNA结合活性，这与抑制NF-κ B调控蛋白Bcl-2、Bcl-xL、cyclin D1和survivin的表达有关。NF-κB报告基因检测结果表明，RB能抑制NF-κB的组成性激活和LPS（脂多糖）诱导的NF-κB的激活。过表达RelA/p65可挽救RB诱导的细胞死亡，而敲低RelA/p65可显著促进RB介导的细胞增殖抑制作用，提示NF-κB通路在此过程中起重要作用。我们进一步分析了RB的体内抗肿瘤活性。RB主要通过抑制肿瘤组织中NF-κB的活性来抑制RM-1移植瘤的生长和诱导肿瘤细胞凋亡。此外，DNA微阵列数据揭示了响应RB治疗的与细胞增殖、凋亡、侵袭和转移相关的基因表达的总体变化。因此，我们的研究结果表明RB通过靶向PCa细胞中的NF-κB通路发挥其抗肿瘤作用，这可能是RB在其他类型癌症中的抗肿瘤作用的一般机制。
Previously, we reported that retigeric acid B (RB), a natural pentacyclic triterpenic acid isolated from lichen, inhibited cell growth and induced apoptosis in androgen-independent prostate cancer (PCa) cells. However, the mechanism of action of RB remains unclear. In this study, we found that using PC3 and DU145 cells as models, RB inhibited phosphorylation levels of IκBα and p65 subunit of NF-κB in a time- and dosage-dependent manner. Detailed study revealed that RB blocked the nuclear translocation of p65 and its DNA binding activity, which correlated with suppression of NF-κB-regulated proteins including Bcl-2, Bcl-xL, cyclin D1 and survivin. NF-κB reporter assay suggested that RB was able to inhibit both constitutive activated-NF-κB and LPS (lipopolysaccharide)-induced activation of NF-κB. Overexpression of RelA/p65 rescued RB-induced cell death, while knockdown of RelA/p65 significantly promoted RB-mediated inhibitory effect on cell proliferation, suggesting the crucial involvement of NF-κB pathway in this event. We further analyzed antitumor activity of RB in in vivo study. In C57BL/6 mice carrying RM-1 homografts, RB inhibited tumor growth and triggered apoptosis mainly through suppressing NF-κB activity in tumor tissues. Additionally, DNA microarray data revealed global changes in the gene expression associated with cell proliferation, apoptosis, invasion and metastasis in response to RB treatment. Therefore, our findings suggested that RB exerted its anti-tumor effect by targeting the NF-κB pathway in PCa cells, and this could be a general mechanism for the anti-tumor effect of RB in other types of cancers as well.
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影响因子：
3.8
作者：
Chintharlapalli S;Papineni S;Lei P;Pathi S;Safe S
通讯作者：
Safe S
DOI：
10.1007/978-1-60327-530-9_10
发表时间：
2009-01-01
期刊：
INFLAMMATION AND CANCER: METHODS AND PROTOCOLS, VOL 2: MOLECULAR ANALYSIS AND PATHWAYS
影响因子：
--
作者：
Mauro, Claudio;Zazzeroni, Francesca;Franzoso, Guido
通讯作者：
Franzoso, Guido
影响因子：
4.4
作者：
Takada, Y;Aggarwal, BB
通讯作者：
Aggarwal, BB
影响因子：
4.5
作者：
Lessard, L;Mes-Masson, AM;Saad, F
通讯作者：
Saad, F
影响因子：
6.4
作者：
Park, Byoungduck;Sung, Bokyung;Yadav, Vivek R.;Cho, Sung-Gook;Liu, Mingyao;Aggarwal, Bharat B.
通讯作者：
Aggarwal, Bharat B.