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Role of endogenous and exogenous nitric oxide, carbon monoxide and hydrogen sulfide in HCT116 colon cancer cell proliferation

机译:内源性和外源氧化氮,一氧化碳和硫化氢在HCT116结肠癌细胞增殖中的作用

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The role of the three gasotransmitter systems - nitric oxide (NO), carbon monoxide (CO) and hydrogen sulfide (H2S)- in cancer cells has not yet been studied simultaneously in the same experimental system. We measured the expression of NO and CO and H2S generating enzymes in primary colon cancer tissues and HCT116 colon cancer cells, and evaluated the effect of their pharmacological inhibition or pharmacological donation on cell proliferation. Increased expression of iNOS, nNOS, HO-1, CBS and 3-MST was detected in colon cancer. Inhibitors of NOS, HO-1/2, CBS/CSE and 3-MST, at lower concentrations, slightly stimulated HCT116 cell proliferation, but inhibited proliferation at higher concentrations. Donors of NO, CO or H2S inhibited HCT116 proliferation in a concentration-dependent manner. Inhibition of the cGMP/VASP pathway, Akt and p44/42 MAPK (Erkl/2) inhibited HCT116 cell proliferation. Endogenous NO and H2S biosynthesis were found to play a role in the maintenance of the activity of the cGMP/VASP pathway in HCT116 cells. We conclude that each of the three gasotransmitters play similar, bell-shaped roles in the control of HCT116 cell proliferation: endogenously produced NO, CO and H2S, at an optimal concentration, support HCT116 proliferation; inhibition of their production (which decreases gasotransmitter levels below optimal concentrations) as well as exogenous delivery of these gasotransmitters (which increases gasotransmitter levels above optimal concentrations) suppresses colon cancer cell proliferation. The current data give a mechanistic explanation for the paradoxical finding that both inhibitors and donors of NO, CO and H2S exert anticancer actions in cancer cells. (C) 2017 Elsevier Inc. All rights reserved.
机译:在相同的实验系统中尚未在同一实验系统中同时研究三种汽油转体系统 - 一氧化氮(NO),一氧化碳(CO)和硫化氢(H2S) - 癌细胞中的作用。我们测量了在原中结肠癌组织和HCT116结肠癌细胞中产生酶的NO和CO和H 2 S的表达,并评估了它们的药理学抑制或药理学捐赠对细胞增殖的影响。在结肠癌中检测到Inos,NNO,HO-1,CBS和3-MST的表达增加。 NoS,HO-1/2,CBS / CSE和3-MST的抑制剂,较低浓度,略微刺激HCT116细胞增殖,但在较高浓度下抑制增殖。 NO,CO或H 2S的供体以浓度依赖性方式抑制HCT116增殖。抑制CGMP / VASP途径,AKT和P44 / 42 MAPK(ERKL / 2)抑制了HCT116细胞增殖。发现内源性NO和H 2 S生物合成在维持HCT116细胞中的CGMP / VASP途径的活性中起作用。我们得出结论,三种汽油转化器中的每一个在HCT116细胞增殖控制中起相似,钟形作用:内源性不含,CO和H2S,以最佳的浓度,支持HCT116增殖;抑制它们的生产(降低了最佳浓度低于最佳浓度的气体转化液)以及这些气体转化器的外源递送(增加了高于最佳浓度的气体转化液)抑制了结肠癌细胞增殖。目前的数据为矛盾的发现提供了一种机制解释,即NO,CO和H2S的抑制剂和供体在癌细胞中发挥抗癌动作。 (c)2017年Elsevier Inc.保留所有权利。

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