Metformin disrupts crosstalk between G protein-coupled receptor and insulin receptor signaling systems and inhibits pancreatic cancer growth.
Metformin disrupts crosstalk between G protein-coupled receptor and insulin receptor signaling systems and inhibits pancreatic cancer growth.
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DOI：
10.1158/0008-5472.can-09-0418
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发表时间：
2009-08-15
期刊：
影响因子：
11.2
通讯作者：
Rozengurt E
中科院分区：
文献类型：
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作者：
Kisfalvi K;Eibl G;Sinnett-Smith J;Rozengurt E
最近，我们在人胰腺癌细胞中发现了胰岛素和g蛋白偶联受体（GPCR）信号通路之间的一种新的串扰。胰岛素通过雷帕霉素敏感的mtor依赖途径增强GPCR信号。二甲双胍是治疗2型糖尿病最广泛使用的药物，它可以激活AMP激酶（AMPK），从而负调控mTOR。在这里，我们确定了二甲双胍是否会破坏胰腺癌细胞中胰岛素受体和GPCR信号之间的串扰。用胰岛素（10ng/ml）处理人胰腺癌细胞（PANC-1、MIAPaCa-2、BxPC-3） 5分钟后，GPCR激动剂（如神经紧张素、缓激肽、血管紧张素II）诱导的细胞内[Ca2+]水平明显升高。二甲双胍预处理完全消除了胰岛素诱导的Ca2+信号增强，但不干扰单独使用GPCR激动剂的效果。通过DNA合成和在贴壁或非贴壁条件下培养的细胞数量来测量，胰岛素也增强了GPCR激动剂诱导的生长。低剂量二甲双胍（0.1-0.5 mM）阻断胰岛素和GPCR激动剂诱导的DNA合成、锚定依赖性和独立生长的刺激。二甲双胍处理诱导AMPK在Thr172位点的磷酸化显著和持续增加，而选择性AMPK抑制剂（化合物C，在5μM）逆转了二甲双胍对[Ca2+]i和DNA合成的影响，表明二甲双胍通过AMPK激活起作用。鉴于这些结果，我们测试了二甲双胍是否抑制胰腺癌的生长。二甲双胍可显著抑制裸鼠侧壁移植的MIAPaCa-2和PANC-1细胞的生长。该结果提高了二甲双胍可能成为人类胰腺癌新治疗策略的潜在候选药物的可能性。
Recently we identified a novel crosstalk between insulin and G-protein-coupled receptor (GPCR) signaling pathways in human pancreatic cancer cells. Insulin enhanced GPCR signaling through a rapamycin-sensitive mTOR-dependent pathway. Metformin, the most widely used drug in the treatment of type-2 diabetes, activates AMP kinase (AMPK), which negatively regulates mTOR. Here, we determined whether metformin disrupts crosstalk between insulin receptor and GPCR signaling in pancreatic cancer cells. Treatment of human pancreatic cancer cells (PANC-1, MIAPaCa-2, BxPC-3) with insulin (10ng/ml) for 5 min markedly enhanced the increase in intracellular [Ca2+] induced by GPCR agonists (e.g. neurotensin, bradykinin, angiotensin II). Metformin pretreatment completely abrogated insulin-induced potentiation of Ca2+ signaling but did not interfere with the effect of GPCR agonists alone. Insulin also enhanced GPCR agonist-induced growth, measured by DNA synthesis, and numbers of cells cultured in adherent or non-adherent conditions. Low doses of metformin (0.1-0.5 mM) blocked stimulation of DNA synthesis, anchorage-dependent and independent growth induced by insulin and GPCR agonists. Treatment with metformin induced striking and sustained increase in the phosphorylation of AMPK at Thr172 and a selective AMPK inhibitor (compound C, at 5μM) reversed the effects of metformin on [Ca2+]i, and DNA synthesis, indicating that metformin acts through AMPK activation. In view of these results we tested whether metformin inhibits pancreatic cancer growth. Administration of metformin significantly decreased the growth of MIAPaCa-2 and PANC-1 cells xenografted on the flank of nude mice. The results raise the possibility that metformin could be a potential candidate in novel treatment strategies for human pancreatic cancer.