20(S)-25-methoxyl-dammarane-3β, 12β, 20-triol negatively regulates activation of STAT3 and ERK pathways and exhibits anti-cancer effects in HepG2 cells
20(S)-25-methoxyl-dammarane-3β, 12β, 20-triol negatively regulates activation of STAT3 and ERK pathways and exhibits anti-cancer effects in HepG2 cells
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20(S)-25-methoxyl-dammarane-3 beta, 12 beta, 20-triol 负调节 STAT3 和 ERK 通路的激活，并在 HepG2 细胞中表现出抗癌作用
DOI：
10.1007/s10495-017-1416-9
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发表时间：
2017-11-01
期刊：
影响因子：
7.2
通讯作者：
Li, Yu-Xin
中科院分区：
文献类型：
--
作者：
Ai, Hui-Han;Zhou, Zi-Long;Li, Yu-Xin
促炎细胞因子白细胞介素6（IL-6）通过激活其下游的JAK/STAT 3和Ras/ERK信号通路参与多种恶性肿瘤的细胞生长、增殖和抗凋亡活性。为了筛选IL-6信号转导抑制剂，我们构建了STAT 3和ERK双通路应答的荧光素酶报告载体（Co.RE）。在几种候选物中，天然化合物20（S）-25-甲基-达玛烷-3 β，12 β，20-三醇（25-OCH 3-PPD，GS 25）被鉴定为明显抑制Co. RE的荧光素酶活性。证实GS 25确实抑制STAT 3和ERK途径的激活以及IL-6下游靶基因的表达，并且主要通过诱导细胞周期停滞和凋亡来降低HepG 2细胞的存活率。有趣的是，相对于正常肝L02细胞，GS 25显示出对HepG 2细胞活力的优先抑制。进一步的研究表明，GS 25不能像在HepG 2细胞中那样有效地诱导L02细胞凋亡和阻断STAT 3和ERK通路的激活，这可能导致GS 25对恶性和正常肝细胞的不同作用。此外，研究发现GS 25在较高浓度下可以有效抑制内源性STAT 3的表达，并显着诱导HepG 2细胞中p38磷酸化，从而介导其抗癌作用。最后，我们证明了GS 25也抑制HepG 2异种移植小鼠中的肿瘤生长。综上所述，这些发现表明GS 25通过多种机制发挥其对HepG 2细胞的抗癌作用，并具有用作IL-6信号传导抑制剂的潜力。因此，GS 25可被开发为对正常肝组织具有低毒性的肝癌以及其它炎症相关疾病的治疗。
The pro-inflammatory cytokine interleukin 6 (IL-6), via activating its downstream JAK/STAT3 and Ras/ERK signaling pathways, is involved in cell growth, proliferation and anti-apoptotic activities in various malignancies. To screen inhibitors of IL-6 signaling, we constructed a STAT3 and ERK dual-pathway responsive luciferase reporter vector (Co.RE). Among several candidates, the natural compound 20(S)-25-methoxyl-dammarane-3 beta, 12 beta, 20-triol (25-OCH3-PPD, GS25) was identified to clearly inhibit the luciferase activity of Co.RE. GS25 was confirmed to indeed inhibit activation of both STAT3 and ERK pathways and expression of downstream target genes of IL-6, and to predominantly decrease the viability of HepG2 cells via induction of cell cycle arrest and apoptosis. Interestingly, GS25 showed preferential inhibition of HepG2 cell viability relative to normal liver L02 cells. Further investigation showed that GS25 could not induce apoptosis and block activation of STAT3 and ERK pathways in L02 cells as efficiently as in HepG2 cells, which may result in differential effects of GS25 on malignant and normal liver cells. In addition, GS25 was found to potently suppress the expression of endogenous STAT3 at a higher concentration and dramatically induce p38 phosphorylation in HepG2 cells, which could mediate its anti-cancer effects. Finally, we demonstrated that GS25 also inhibited tumor growth in HepG2 xenograft mice. Taken together, these findings indicate that GS25 elicits its anti-cancer effects on HepG2 cells through multiple mechanisms and has the potential to be used as an inhibitor of IL-6 signaling. Thus, GS25 may be developed as a treatment for hepatocarcinoma with low toxicity on normal liver tissues as well as other inflammation-associated diseases.