Effects of insulin on human pancreatic cancer progression modeled in vitro.
Effects of insulin on human pancreatic cancer progression modeled in vitro.
复制标题
胰岛素对体外建模的人类胰腺癌进展的影响。
DOI：
10.1186/1471-2407-14-814
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发表时间：
2014-11-06
期刊：
影响因子：
3.8
通讯作者：
Johnson JD
中科院分区：
文献类型：
--
作者：
Chan MT;Lim GE;Skovsø S;Yang YH;Albrecht T;Alejandro EU;Hoesli CA;Piret JM;Warnock GL;Johnson JD
胰腺癌是最致命的癌症之一，但对它的研究仍然很少，了解也很少。高胰岛素血症已被报道为胰腺癌的危险因素，而与肥胖和2型糖尿病相关的高胰岛素血症的迅速上升预示着癌症发病率的上升。然而，胰岛素在胰腺癌进展不同阶段的作用仍不明确。在这里，我们考察了不同剂量的胰岛素对三种人类细胞模型中信号、增殖和存活的影响，这三种细胞模型代表了胰腺癌进展的三个阶段：原发胰腺管细胞、HPDE永生化胰腺导管细胞系和PANC1转移胰腺癌细胞系。用不同剂量的胰岛素处理细胞，并通过活细胞成像和XTT分析来跟踪它们的增殖/活性。通过免疫印迹检测AKT和ERK信号通路的信号转导。AKT和ERK信号通路的抑制剂被用来确定这些通路对每个细胞模型存活的相对贡献。虽然AKT和ERK的磷酸化表明所有三种类型的细胞都对胰岛素有反应，但我们发现不同类型的细胞在胰岛素依赖的增殖、细胞活力和细胞存活率方面存在显著差异。高浓度胰岛素可增加PANC1和HPDE细胞的数量，但不影响原代培养的导管细胞的增殖。胰岛素可提高原代导管细胞和HPDE细胞的细胞存活率。此外，我们发现原代细胞更依赖于AKT信号，而HPDE细胞和PANC1细胞更依赖于RAF/ERK信号。我们的数据表明，过量的胰岛素信号可能有助于人永生化胰腺管细胞和转移性胰腺癌细胞的增殖和存活，但对正常成人胰腺导管细胞没有影响。这些数据表明，参与细胞存活的信号通路可能在胰腺癌进展过程中重新连接。
Pancreatic adenocarcinoma is one of the most lethal cancers, yet it remains understudied and poorly understood. Hyperinsulinemia has been reported to be a risk factor of pancreatic cancer, and the rapid rise of hyperinsulinemia associated with obesity and type 2 diabetes foreshadows a rise in cancer incidence. However, the actions of insulin at the various stages of pancreatic cancer progression remain poorly defined. Here, we examined the effects of a range of insulin doses on signalling, proliferation and survival in three human cell models meant to represent three stages in pancreatic cancer progression: primary pancreatic duct cells, the HPDE immortalized pancreatic ductal cell line, and the PANC1 metastatic pancreatic cancer cell line. Cells were treated with a range of insulin doses, and their proliferation/viability were tracked via live cell imaging and XTT assays. Signal transduction was assessed through the AKT and ERK signalling pathways via immunoblotting. Inhibitors of AKT and ERK signalling were used to determine the relative contribution of these pathways to the survival of each cell model. While all three cell types responded to insulin, as indicated by phosphorylation of AKT and ERK, we found that there were stark differences in insulin-dependent proliferation, cell viability and cell survival among the cell types. High concentrations of insulin increased PANC1 and HPDE cell number, but did not alter primary duct cell proliferation in vitro. Cell survival was enhanced by insulin in both primary duct cells and HPDE cells. Moreover, we found that primary cells were more dependent on AKT signalling, while HPDE cells and PANC1 cells were more dependent on RAF/ERK signalling. Our data suggest that excessive insulin signalling may contribute to proliferation and survival in human immortalized pancreatic ductal cells and metastatic pancreatic cancer cells, but not in normal adult human pancreatic ductal cells. These data suggest that signalling pathways involved in cell survival may be rewired during pancreatic cancer progression.
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影响因子：
2.9
作者：
Deer EL;González-Hernández J;Coursen JD;Shea JE;Ngatia J;Scaife CL;Firpo MA;Mulvihill SJ
通讯作者：
Mulvihill SJ
有效使用 PI3K 和 MEK 抑制剂治疗突变型 Kras G12D 和 PIK3CA H1047R 小鼠肺癌。
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
4.8
作者：
Beith, Jennifer L.;Alejandro, Emilyn U.;Johnson, James D.
通讯作者：
Johnson, James D.
影响因子：
5
作者：
Coughlin, SS;Calle, EE;Thun, MJ
通讯作者：
Thun, MJ
影响因子：
4.8
作者：
Alejandro, Emilyn U.;Johnson, James D.
通讯作者：
Johnson, James D.