Nicotine induces self-renewal of pancreatic cancer stem cells via neurotransmitter-driven activation of sonic hedgehog signalling.
Nicotine induces self-renewal of pancreatic cancer stem cells via neurotransmitter-driven activation of sonic hedgehog signalling.
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DOI：
10.1016/j.ejca.2015.10.003
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发表时间：
2016-01
期刊：
影响因子：
--
通讯作者：
Schuller HM
中科院分区：
文献类型：
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作者：
Al-Wadei MH;Banerjee J;Al-Wadei HA;Schuller HM
具有干细胞特征的胰腺癌细胞的小亚群驱动肿瘤的发生、进展和转移。更好地了解癌症干细胞的调控可能会导致更有效的癌症预防和治疗。我们已经证明，胰腺癌细胞系的增殖和迁移是由烟碱受体介导的应激神经递质释放激活的，γ-氨基丁酸（GABA）逆转了这种反应。然而，所观察到的GABA的癌症抑制作用只有在GABA抑制胰腺癌干细胞（PCSC）以及构成大多数癌组织和细胞系的更分化的癌细胞时才会在临床上成功。使用通过细胞分选和通过来自胰腺癌细胞系Panc-1的球体形成测定从两名胰腺癌患者分离的PCSC，我们测试了尼古丁诱导PCSC自我更新的假设。尼古丁乙酰胆碱受体（nAChRs）α3、α4、α5和α7表达，慢性暴露于尼古丁增加了这些受体的蛋白表达。免疫分析显示，胰腺癌干细胞产生应激神经递质肾上腺素和去甲肾上腺素以及抑制性神经递质GABA。慢性尼古丁显著增加应激神经递质和音刺猬（SHH）的产生，同时诱导Gli 1蛋白和减少GABA。GABA处理抑制SHH和Gli 1的诱导。球体形成和MTT试验表明，尼古丁诱导的自我更新和细胞增殖显着增加，GABA阻断的反应。我们的数据表明，尼古丁增加了SHH介导的胰腺癌干细胞的恶性潜能，而GABA阻止了这些作用。
A small subpopulation of pancreatic cancer cells with characteristics of stem cells drive tumor initiation, progression and metastasis. A better understanding of the regulation of cancer stem cells may lead to more effective cancer prevention and therapy. We have shown that the proliferation and migration of pancreatic cancer cell lines is activated by the nicotinic receptor-mediated release of stress neurotransmitters, responses reversed by γ-aminobutyric acid (GABA). However, the observed cancer inhibiting effects of GABA will only succeed clinically if GABA inhibits pancreatic cancer stem cells (PCSCs) in addition to the more differentiated cancer cells that comprise the majority of cancer tissues and cell lines. Using PCSCs isolated from two pancreatic cancer patients by cell sorting and by spheroid formation assay from pancreatic cancer cell line Panc-1, we tested the hypothesis that nicotine induces the self-renewal of PCSCs. Nicotinic acetylcholine receptors (nAChRs) α3, α4, α5 and α7 were expressed and chronic exposure to nicotine increased the protein expression of these receptors. Immunoassays showed that pancreatic cancer stem cells produced the stress neurotransmitters epinephrine and norepinephrine and the inhibitory neurotransmitter GABA. Chronic nicotine significantly increased the production of stress neurotransmitters and sonic hedgehog (SHH) while inducing Gli1 protein and decreasing GABA. GABA treatment inhibited the induction of SHH and Gli1. Spheroid formation and MTT assays showed significant nicotine-induced increases in self renewal and cell proliferation, responses blocked by GABA. Our data suggest that nicotine increases the SHH-mediated malignant potential of pancreatic cancer stem cells and that GABA prevents these effects.