| 孙丽云,陈刚,张顺康,等.二甲双胍对不同雌激素受体状态乳腺癌细胞的放射增敏作用及其机制研究[J].中华放射医学与防护杂志,2018,38(5):327-334.Sun Liyun,Chen Gang,Zhang Shunkang,et al.Effects of metformin on radiosensitivity of breast carcinoma cells with different estrogen receptors stasus and its mechanism[J].Chin J Radiol Med Prot,2018,38(5):327-334 |
| 二甲双胍对不同雌激素受体状态乳腺癌细胞的放射增敏作用及其机制研究 |
| Effects of metformin on radiosensitivity of breast carcinoma cells with different estrogen receptors stasus and its mechanism |
| 投稿时间：2017-12-06 |
| DOI：10.3760/cma.j.issn.0254-5098.2018.05.002 |
| 中文关键词: 二甲双胍 放射增敏 乳腺癌细胞 雌激素受体 凋亡 |
| 英文关键词:Metformin Radiosensitization Breast carcinoma cells Estrogen receptor Apoptosis |
| 基金项目:首都卫生发展科研专项（2014-1-5124） |
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| 中文摘要: |
| 目的 探讨二甲双胍对不同雌激素受体（ER）状态乳腺癌细胞MCF-7和MDA-MB-231是否具有放射增敏作用，并对其机制进行初步探索。方法 取指数生长期的人乳腺癌细胞MCF-7和MDA-MB-231，分为对照组、二甲双胍组、单纯照射组和二甲双胍联合照射组。采用MTT法测定二甲双胍对细胞的增殖抑制作用；克隆形成实验评估二甲双胍对乳腺癌细胞的放射增敏作用；碘化丙啶（PI）染色法检测细胞周期；Hoechst 33342染色法检测细胞凋亡率；Western blot法检测各组p-AMPK、p-mTOR蛋白的表达情况。结果 不同浓度二甲双胍对这两种细胞均具有明显的增殖抑制作用，且呈剂量依赖性。在乳腺癌细胞MCF-7和MDA-MB-231中，二甲双胍联合照射组的Dq、D0和SF2值均较单纯照射组明显降低（MCF-7：t=9.305、14.528、13.708，P<0.05；MDA-MB-231：t=19.560、16.893、36.048，P<0.05），放射增敏比（SERD0）分别为1.29和1.21。二甲双胍联合照射组与单纯照射组相比，G2/M期阻滞更明显（t=6.103、38.431，P<0.05），增加了放射诱导的细胞凋亡（t=9.143、14.561，P<0.05）。在MCF-7细胞中，二甲双胍联合照射组p-AMPK的表达明显高于其他处理组（t=35.194、8.647、10.316，P<0.05），但在MDA-MB-231细胞中，p-AMPK的表达未见明显变化（P>0.05）；而对p-mTOR蛋白的抑制作用在这两种细胞中均可见到，差异有统计学意义（MCF-7：t=80.133、31.820、11.308，P<0.05；MDA-MB-231：t=12.436、15.757、8.402，P<0.05）。结论 二甲双胍对不同ER状态乳腺癌细胞（MCF-7和MDA-MB-231）均有放射增敏作用，其作用机制可能是通过激活AMPK或非AMPK依赖的途径，抑制mTOR信号级联通路，以及增加细胞G2/M期阻滞，诱导细胞凋亡等途径实现的。 |
| 英文摘要: |
| Objective To investigate the effects of metformin on the radiosensitivity of breast carcinoma cells with different estrogen receptors stasus (MCF-7 and MDA-MB-231) and to explore the underlying mechanisms. Methods Two cell lines, MCF-7 and MDA-MB-231 in logarithmic phase were divided into four groups:control group, drug group (metformin), irradiation group and experimental group (irradiation plus metformin). MTT assay and the clonogenic assay were performed to evaluate the effects of metformin on the proliferation and survival of breast carcinoma cell lines, respectively. The change of cell cycle distribution and apoptosis rates were measured by propidium iodide (PI) and Hoechst 33342 staining analysis repectively. Western blot was used to detect the expression of p-AMPK and p-mTOR. Resutls Metformin could obviously inhibit the proliferation of the two breast carcinoma cell lines in a dose dependent manner. The cloning formation capacity was decreased in the group of metformin plus irradiation,which displayed the values of Dq, D0 and SF2 significantly lower than those of irradiation alone group (MCF-7:t=9.305, 14.528, 13.708, P<0.05;MDA-MB-231:t=19.560, 16.893, 36.048, P<0.05), and the sensitizing enhance rate (SER) of D0 were 1.29 and 1.21 for MCF-7 and MDA-MB-231 cell lines, respectively. Compared with irradiation alone, metformin plus irradiation obviously increased the proportion of cells in the G2/M phase in both cell lines (t=6.103, 38.431, P<0.05). Metformin plus irradiation also enhanced radiation-induced apoptosis in both cell lines so that the apoptosis rates were higher than that in the metformin group or irradiation alone group (t=9.143, 14.561, P<0.05). In MCF-7 cell lines, the expression of p-AMPK in the metformin combined with irradiation group was significantly higher than other treatment groups (t=35.194, 8.647, 10.316, P<0.05), but no significant changes of p-AMPK expression in MDA-MB-231 cell lines was observed (P>0.05). While inhibition of p-mTOR by metformin was observed in both cell lines (MCF-7:t=80.133, 31.820, 11.308, P<0.05;MDA-MB-231:t=12.436, 15.757, 8.402, P<0.05). Conclusions This study suggests that metformin possessed a strong radiosensitizing potential in both breast carcinoma cell lines of MCF-7 (ER positive) and MDA-MB-231 (ER negative). This radiosensitizing effect may result from the activation of AMPK or AMPK-independent pathway, inhibition of mTOR signaling pathway, and the enhancement of radiation-induced G\-2/M phase arrest and cell apoptosis after metformin treatment. |
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