High Glucose-Mediated STAT3 Activation in Endometrial Cancer Is Inhibited by Metformin: Therapeutic Implications for Endometrial Cancer.
High Glucose-Mediated STAT3 Activation in Endometrial Cancer Is Inhibited by Metformin: Therapeutic Implications for Endometrial Cancer.
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二甲双胍对子宫内膜癌的高葡萄糖介导的STAT3激活抑制：对子宫内膜癌的治疗意义。
DOI：
10.1371/journal.pone.0170318
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Selvendiran K
中科院分区：
文献类型：
--
作者：
Wallbillich JJ;Josyula S;Saini U;Zingarelli RA;Dorayappan KD;Riley MK;Wanner RA;Cohn DE;Selvendiran K
STAT3在子宫内膜癌中过度表达，糖尿病是I型子宫内膜癌发生的危险因素。因此，我们研究了葡萄糖浓度是否影响1型子宫内膜癌中STAT3的表达，以及二甲双胍是否可能抑制这种STAT3的表达。在Ishikawa(1级)子宫内膜癌细胞中，用实时定量聚合酶链式反应(QPCR)检测STAT3及其靶蛋白在低、中、高浓度葡萄糖介质中的表达。用二甲双胍处理Ishikawa细胞，用细胞增殖、存活、迁移和泛素检测，以及Western印迹和qPCR检测。用Western印迹法检测转染STAT3过表达载体的Ishikawa细胞在二甲双胍作用下细胞凋亡蛋白的表达。采用裸鼠移植瘤模型研究二甲双胍的体内药效。在高糖培养的Ishikawa细胞中，STAT3及其靶蛋白的表达增加。在体外，二甲双胍抑制细胞的增殖、存活和迁移，但诱导细胞凋亡。二甲双胍降低pSTAT3ser727、总STAT3及其相关的细胞存活和抗凋亡蛋白的表达水平。此外，二甲双胍治疗与pSTAT3 ser727降解增加有关。在Ishikawa细胞中，STAT3过表达对凋亡蛋白的表达无明显影响。在体内，二甲双胍治疗导致了肿瘤重量的减少以及其靶蛋白STAT3、pSTAT3ser727的减少。这些结果表明，STAT3在1型子宫内膜癌中的表达受到高糖环境的刺激和二甲双胍的抑制。
STAT3 is over-expressed in endometrial cancer, and diabetes is a risk factor for the development of type 1 endometrial cancer. We therefore investigated whether glucose concentrations influence STAT3 expression in type 1 endometrial cancer, and whether such STAT3 expression might be inhibited by metformin. In Ishikawa (grade 1) endometrial cancer cells subjected to media with low, normal, or high concentrations of glucose, expression of STAT3 and its target proteins was evaluated by real-time quantitative PCR (qPCR). Ishikawa cells were treated with metformin and assessed with cell proliferation, survival, migration, and ubiquitin assays, as well as Western blot and qPCR. Expression of apoptosis proteins was evaluated with Western blot in Ishikawa cells transfected with a STAT3 overexpression plasmid and treated with metformin. A xenograft tumor model was used for studying the in vivo efficacy of metformin. Expression of STAT3 and its target proteins was increased in Ishikawa cells cultured in high glucose media. In vitro, metformin inhibited cell proliferation, survival and migration but induced apoptosis. Metformin reduced expression levels of pSTAT3 ser727, total STAT3, and its associated cell survival and anti-apoptotic proteins. Additionally, metformin treatment was associated with increased degradation of pSTAT3 ser727. No change in apoptotic protein expression was noticed with STAT3 overexpression in Ishikawa cells. In vivo, metformin treatment led to a decrease in tumor weight as well as reductions of STAT3, pSTAT3 ser727, its target proteins. These results suggest that STAT3 expression in type 1 endometrial cancer is stimulated by a high glucose environment and inhibited by metformin.