大豆异黄酮和染料木黄酮通过破坏AKT/mTOR和MAPK信号通路来抑制子宫内膜癌细胞的增殖。
Novasoy and genistein inhibit endometrial cancer cell proliferation through disruption of the AKT/mTOR and MAPK signaling pathways.
作者信息
Malloy Kim M, Wang Jiandong, Clark Leslie H, Fang Ziwei, Sun Wenchuan, Yin Yajie, Kong Weimin, Zhou Chunxiao, Bae-Jump Victoria L
机构信息
Virginia Tech/Carilion Clinic, Department of Obstetrics and GynecologyBlacksburg, VA.
Division of Gynecologic Oncology, University of North Carolina at Chapel HillChapel Hill, NC. USA.
出版信息
Am J Transl Res. 2018 Mar 15;10(3):784-795. eCollection 2018.
OBJECTIVES
Excess estrogen states, such as those generated by obesity, have long been associated with the development of type I endometrial cancers. Epidemiological studies have linked consumption of isoflavones with a decreased incidence of endometrial malignancy. Thus, our goal was to assess the effect of the isoflavones, novasoy and genistein, on cell proliferation, cell cycle, apoptosis, progesterone receptor (PR) and estrogen receptor-alpha (ERα) expression and the AKT/mTOR and MAPK pathways in endometrial cancer cells.
METHODS
The endometrial cancer cell lines ECC-1 and RL-95-2 were used. Cell proliferation was assessed with MTT assay after exposure to novasoy and genistein at varying concentrations. Cell cycle progression was analyzed by flow cytometry. Apoptosis was assessed by flow cytometery for annexin V expression and ELISA for caspase-3 activity. Expression of ERα, PR and hTERT mRNA were evaluated using real time RT-PCR. Western immunoblotting was performed to evaluate the effects of novasoy and genistein on the AKT/mTOR and MAPK signaling pathways.
RESULTS
Novasoy and genistein inhibited cell growth in a dose-dependent manner in both cell lines through induction of cell cycle G2 arrest and apoptosis. Treatment with novasoy and genistein decreased hTERT expression in a dose-dependent manner. Genistein decreased ERα mRNA expression while increasing PR expression. Genistein induced phosphorylation of p42/44 in a dose dependent manner in both cell lines but reduced phosphorylation of S6 in only the RL-95-2 cells.
CONCLUSIONS
Novasoy and genistein inhibited cell proliferation through varying pathways in different cell lines but included decreased ERα expression and subsequent alteration in the expression of proteins upstream and downstream of the AKT/mTOR and MAPK pathways. Thus, isoflavones may be a promising therapeutic agent in the treatment and prevention of endometrial cancer.
目的
长期以来，诸如肥胖所导致的雌激素过多状态一直与I型子宫内膜癌的发生有关。流行病学研究表明，食用异黄酮与子宫内膜恶性肿瘤发病率降低有关。因此，我们的目标是评估异黄酮（诺瓦大豆异黄酮和染料木黄酮）对子宫内膜癌细胞的细胞增殖、细胞周期、凋亡、孕激素受体（PR）和雌激素受体α（ERα）表达以及AKT/mTOR和MAPK信号通路的影响。
方法
使用子宫内膜癌细胞系ECC-1和RL-95-2。在暴露于不同浓度的诺瓦大豆异黄酮和染料木黄酮后，通过MTT法评估细胞增殖。通过流式细胞术分析细胞周期进程。通过流式细胞术检测膜联蛋白V表达以及通过ELISA检测半胱天冬酶-3活性来评估凋亡。使用实时RT-PCR评估ERα、PR和hTERT mRNA的表达。进行蛋白质免疫印迹以评估诺瓦大豆异黄酮和染料木黄酮对AKT/mTOR和MAPK信号通路的影响。
结果
诺瓦大豆异黄酮和染料木黄酮通过诱导细胞周期G2期阻滞和凋亡，以剂量依赖的方式抑制两种细胞系的细胞生长。用诺瓦大豆异黄酮和染料木黄酮处理以剂量依赖的方式降低hTERT表达。染料木黄酮降低ERα mRNA表达，同时增加PR表达。染料木黄酮在两种细胞系中均以剂量依赖的方式诱导p42/44磷酸化，但仅在RL-95-2细胞中降低S6磷酸化。
结论
诺瓦大豆异黄酮和染料木黄酮通过不同细胞系中的不同途径抑制细胞增殖，但包括降低ERα表达以及随后改变AKT/mTOR和MAPK信号通路上下游蛋白质的表达。因此，异黄酮可能是治疗和预防子宫内膜癌的一种有前景的治疗药物。
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