张明亮,潘成武,王岗,金功圣,钱军.二氢杨梅素通过抑制胰岛素样生长因子1受体下游磷脂酰肌醇3-激酶/蛋白激酶B信号途径增强赫赛汀对乳腺癌细胞的抑制作用[J].转化医学杂志,2017,6(6):340-344
二氢杨梅素通过抑制胰岛素样生长因子1受体下游磷脂酰肌醇3-激酶/蛋白激酶B信号途径增强赫赛汀对乳腺癌细胞的抑制作用
Dihydromyricetin enhances herceptin sensitivity to breast cancer cells through inhibiting the insulin like growth factor 1 receptor downstream phosphatidylinositol 3 kinase/protein kinase B signaling pathway
  
DOI:
中文关键词:  二氢杨梅素  赫赛汀  人表皮生长因子受体2  胰岛素样生长因子1受体  信号通路
英文关键词:Dihydromyricetin (DMY)  Herceptin  Human epidermal growth factor receptor 2 (HER2)  Insulin like growth factor 1 receptor (IGF1R)  Signal pathway
基金项目:安徽省教育厅一般项目(KJ2015B093by)
作者单位
张明亮 蚌埠医学院第一附属医院肿瘤外科 
潘成武 蚌埠医学院第一附属医院肿瘤外科 
王岗 蚌埠医学院第一附属医院肿瘤外科 
金功圣 蚌埠医学院第一附属医院肿瘤外科 
钱军 蚌埠医学院第一附属医院肿瘤外科 
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中文摘要:
      目的观察胰岛素样生长因子1受体(insulinlike growth factor 1 receptor,IGF1R)下游磷脂酰肌醇3激酶/蛋白激酶B(phosphatidylinositol-3kinase/protein kinase B,PI3K/PKB)信号激活对赫赛汀敏感性的影响,探讨二氢杨梅素(dihydromyricetin,DMY)增强赫赛汀敏感性的机制。方法大剂量胰岛素样生长因子1(insulinlike growth factor-1,IGF1)作用乳腺癌SKBR3细胞,激活IGF1R及其下游PI3K/PKB信号通路。分别给予赫赛汀、DMY、DMY联合赫赛汀作用,Western Blot检测细胞受体分子IGF1R、人表皮生长因子受体2(human epidermal growth factor receptor-2,HER2)及下游信号蛋白胰岛素受体底物1(insulin receptor substrates 1,IRS1)、PKB、第10号染色体缺失的磷酸酶及张力蛋白同源基因(phosphatase and tensin homolog deleted on chromosome ten gene,PTEN)表达及磷酸化水平变化;3-(4,5-二甲基噻唑-2)-2,5-二苯基四氮唑溴盐法、流式细胞仪和Transwell小室侵袭实验分别检测肿瘤细胞增殖活性、凋亡及侵袭性变化。结果亲代SKBR3细胞经大剂量IGF1作用后,细胞内IRS1磷酸化水平显著升高(P<0.01),PKB磷酸化水平先缓慢上升、后逐渐平稳,PTEN表达水平显著下降差异有统计学意义(P<0.01); DMY可以显著降低细胞内IRS1(P<0.01)及PKB(P<0.01)磷酸化水平,提高PTEN表达水平(P<0.01);DMY联合赫赛汀作用可显著降低细胞的侵袭能力(P<0.01)、增强细胞凋亡率(P<0.01)。结论IGF1激活IGF1R下游PI3K/PKB信号通路可能是导致SKBR3细胞对赫赛汀产生耐药的原因之一,DMY能够通过抑制PI3K/PKB信号途径增强赫赛汀的敏感度。
英文摘要:
      ObjectiveTo observe the influence of herceptin sensitivity after the phosphatidylinositol 3kinase/protein kinase B (PI3K/PKB) signaling pathway activated in SKBR3 cells, and investigate the cooperative mechanism of dihydromyricetin (DMY) enhancing the sensitivity of herceptin to SKBR3 cells. MethodsPI3K/PKB signal pathway was activated by the high dose of insulinlike growth factor 1 (IGF1) effected on IGF1 receptor (IGF1R) in SKBR3 cells. SKBR3 cells were treated with DMY, herceptin, DMY combined with herceptin respectively after cultured by high dose of IGF1, western blot was used to detect the expression of IGF1R, human epidermal growth factor receptor 2 (HER2) and downstream signaling proteins insulin receptor substrates 1 (IRS1), PKB, phosphatase and tensin homolog deleted on chromosome ten (PTEN) and the phosphorylation level of the molecules; 3-(4,5-dimethyl-2-thiazolyl)-2,5diphenyl-2-H-tetrazolium bromide (MTT) assay, transwell migration experiment and flow cytometry were used to observe the proliferation, migration and apoptosis of tumor cells. ResultsThe IRS1 protein phosphorylation level increased significantly (P<0.01), PKB protein phosphorylation level rose slowly and then became stable gradually, and the expression level of PTEN decreased significantly in tumor cells after they cultured by high dose of IGF1 (P<0.01); DMY could significantly decrease the levels of IRS1 (P<0.01), PKB protein phosphorylation (P<0.01), and increase the expression level of PTEN (P<0.01); DMY combined with herceptin treatment could significantly reduce the cells migration ability (P<0.01), improve the cells apoptosis rate (P<0.01). ConclusionIGF1R downstream PI3K/PKB signaling pathway abnormal activation leads to herceptin resistant to SKBR3 cells, DMY could recover the sensibility of herceptin by inhibiting PI3K/PKB signal pathway.
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