Diindolylmethane suppresses ovarian cancer growth and potentiates the effect of cisplatin in tumor mouse model by targeting signal transducer and activator of transcription 3 (STAT3).
Diindolylmethane suppresses ovarian cancer growth and potentiates the effect of cisplatin in tumor mouse model by targeting signal transducer and activator of transcription 3 (STAT3).
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DOI：
10.1186/1741-7015-10-9
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发表时间：
2012-01-26
期刊：
影响因子：
9.3
通讯作者：
Srivastava SK
中科院分区：
文献类型：
--
作者：
Kandala PK;Srivastava SK
信号转导和转录激活因子3（STAT 3）在大多数卵巢肿瘤中被激活，并使卵巢癌患者对顺铂治疗产生耐药性。我们以前曾报道过二吲哚甲烷（DIM）抑制卵巢癌细胞的生长。然而，迄今为止，DIM诱导生长抑制作用的确切机制尚不清楚。在本报告中，研究了DIM的作用方式。使用六种人卵巢癌细胞系和卵巢肿瘤异种移植动物模型来研究单独或与顺铂组合的二吲哚基甲烷的作用。二吲哚甲烷处理诱导所有六个卵巢癌细胞系的凋亡。DIM以浓度依赖性方式减少STAT 3在Tyr-705和Ser-727上的磷酸化。此外，二吲哚甲烷处理抑制核转位，DNA结合和转录活性的STAT 3。IL-6诱导的STAT 3酪氨酸磷酸化可被DIM阻断，过表达STAT 3可阻断DIM诱导的细胞凋亡。此外，DIM治疗降低了卵巢癌细胞和肿瘤中IL-6的水平。DIM处理还通过抑制缺氧诱导因子1α（HIF-1α）和血管上皮生长因子（VEGF）来抑制细胞侵袭和血管生成。重要的是，二吲哚甲烷处理通过靶向STAT 3增强顺铂在SKOV-3细胞中的作用。每天口服3 mg二吲哚基甲烷并随后给予顺铂基本上抑制了体内肿瘤生长。肿瘤裂解物的蛋白质印迹分析表明细胞凋亡增加和STAT 3活化减少。这些发现为DIM单独或联合用于卵巢癌化学预防和/或化疗的进一步临床研究提供了理论基础。
Signal transducer and activator of transcription 3 (STAT3) is activated in majority of ovarian tumors and confers resistance to cisplatin treatment in patients with ovarian cancer. We have reported previously that diindolylmethane (DIM) inhibits the growth of ovarian cancer cells. However, to date the exact mechanism by which DIM induces growth suppressive effects has not been clear. In this report the mode of action of DIM is investigated. Six human ovarian cancer cell lines and an ovarian tumor xenograft animal model were used to study the effect of diindolylmethane alone or in combination with cisplatin. Diindolylmethane treatment induced apoptosis in all six ovarian cancer cell lines. Phosphorylation of STAT3 at Tyr-705 and Ser-727 was reduced by DIM in a concentration-dependent manner. In addition, diindolylmethane treatment inhibited nuclear translocation, DNA binding, and transcriptional activity of STAT3. Interleukin (IL)-6-induced phosphorylation of STAT3 at Tyr-705 was significantly blocked by DIM. Overexpression of STAT3 by gene transfection blocked DIM-induced apoptosis. In addition, DIM treatment reduced the levels of IL-6 in ovarian cancer cells and in the tumors. DIM treatment also inhibited cell invasion and angiogenesis by suppressing hypoxia-inducible factor 1α (HIF-1α) and vascular epithelial growth factor (VEGF). Importantly, diindolylmethane treatment potentiated the effects of cisplatin in SKOV-3 cells by targeting STAT3. Oral administration of 3 mg diindolylmethane per day and subsequent administration of cisplatin substantially inhibited in vivo tumor growth. Western blotting analysis of tumor lysates indicated increased apoptosis and reduced STAT3 activation. These findings provide a rationale for further clinical investigation of DIM alone or in combination for chemoprevention and/or chemotherapy of ovarian cancer.
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影响因子：
15.9
作者：
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通讯作者：
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影响因子：
8
作者：
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影响因子：
11.2
作者：
Cho SG;Yi Z;Pang X;Yi T;Wang Y;Luo J;Wu Z;Li D;Liu M
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Liu M
影响因子：
5.3
作者：
Banerjee, Sanjeev;Kong, Dejuan;Wang, Zhiwei;Bao, Bin;Hillman, Gilda G.;Sarkar, Fazlul H.
通讯作者：
Sarkar, Fazlul H.
DOI：
10.1111/j.1525-1438.2006.00846.x
发表时间：
2007-05-01
影响因子：
4.8
作者：
Hess, L. M.;Benham-Hutchins, M.;Alberts, D. S.
通讯作者：
Alberts, D. S.