Regulation of nonsmall-cell lung cancer stem cell like cells by neurotransmitters and opioid peptides.
Regulation of nonsmall-cell lung cancer stem cell like cells by neurotransmitters and opioid peptides.
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DOI：
10.1002/ijc.29646
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发表时间：
2015-12-15
影响因子：
6.4
通讯作者：
Schuller HM
中科院分区：
文献类型：
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作者：
Banerjee J;Papu John AM;Schuller HM
非小细胞肺癌（NSCLC）是肺癌的主要类型，预后较差。我们的研究表明，慢性应激通过应激神经递质激活的β -肾上腺素能受体下游cAMP信号传导促进小鼠非小细胞肺癌异种移植，而附带的β受体阻滞剂治疗被报道可以改善非小细胞肺癌患者的临床结果。这些发现提示心理应激促进非小细胞肺癌，而药理学或心理诱导的cAMP降低可能抑制非小细胞肺癌。肿瘤干细胞被认为驱动非小细胞肺癌的发展、进展和对治疗的耐药性。然而，应激性神经递质对它们的潜在调节作用尚未被研究。在目前的研究中，肾上腺素增加了来自三种NSCLC细胞系的肿瘤干细胞样细胞（CSCs）的数量，同时增强细胞内cAMP和干细胞标记物sonic hedgehog （SHH）、醛脱氢酶-1 （ALDH-1）和Gli1，这种作用通过g αi介导的cAMP形成抑制被GABA或dynorphin B逆转。与维持在标准条件下的小鼠相比，应激减轻小鼠模型中的非小细胞肺癌异种移植物的生长明显减少。应激降低血清皮质酮、去甲肾上腺素和肾上腺素水平，抑制性神经递质γ-氨基丁酸（GABA）和阿片肽水平升高。应激降低可显著降低异种移植物组织中的cAMP、VEGF、p-ERK、p-AKT、p-CREB、p-SRc、SHH、ALDH-1和Gli1，而caspase-3和p53则被诱导断裂。我们得出结论，应激神经递质通过多种cAMP介导的途径激活非小细胞肺癌中的CSCs，药理学或心理诱导的cAMP信号减少可能改善非小细胞肺癌患者的临床结果。
Non small-cell lung cancer (NSCLC) is the leading type of lung cancer and has a poor prognosis. We have shown that chronic stress promoted NSCLC xenografts in mice via stress neurotransmitter-activated cAMP signaling downstream of beta-adrenergic receptors and incidental beta-blocker therapy was reported to improve clinical outcomes in NSCLC patients. These findings suggest that psychological stress promotes NSCLC whereas pharmacologically or psychologically induced decreases in cAMP may inhibit NSCLC. Cancer stem cells are thought to drive the development, progression and resistance to therapy of NSCLC. However, their potential regulation by stress neurotransmitters has not been investigated. In the current study, epinephrine increased the number of cancer stem cell like cells (CSCs) from three NSCLC cell lines in spheroid formation assays while enhancing intracellular cAMP and the stem cell markers sonic hedgehog (SHH), aldehyde dehydrogenase-1 (ALDH-1) and Gli1, effects reversed by GABA or dynorphin B via Gαi-mediated inhibition of cAMP formation. The growth of NSCLC xenografts in a mouse model of stress reduction was significantly reduced compared with mice maintained under standard conditions. Stress reduction reduced serum levels of corticosterone, norepinephrine and epinephrine while the inhibitory neurotransmitter γ-aminobutyric acid (GABA) and opioid peptides increased. Stress reduction significantly reduced cAMP, VEGF, p-ERK, p-AKT, p-CREB, p-SRc, SHH, ALDH-1 and Gli1 in xenograft tissues whereas cleaved caspase-3 and p53 were induced. We conclude that stress neurotransmitters activate CSCs in NSCLC via multiple cAMP-mediated pathways and that pharmacologically or psychologically induced decreases in cAMP signaling may improve clinical outcomes in NSCLC patients.