Inhibition of human lung cancer cell growth by angiotensin-(1-7)
Inhibition of human lung cancer cell growth by angiotensin-(1-7)
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DOI：
10.1093/carcin/bgh236
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发表时间：
2004-11-01
期刊：
影响因子：
4.7
通讯作者：
Tallant, EA
中科院分区：
文献类型：
--
作者：
Gallagher, PE;Tallant, EA
血管紧张素-（1-7）[Ang-（1-7）]是肾素-血管紧张素系统的内源性肽激素，具有血管扩张和抗增殖特性。在存在和不存在Ang-（1-7）的情况下，用血清处理人腺癌SK-LU-1和A549细胞以及非小细胞肺癌SK-MES-1细胞，以确定Ang-（1 -7）是否抑制肺癌细胞的生长。Ang-（1-7）在所有三种肺癌细胞系中引起血清刺激生长的显著降低。用Ang-（1-7）处理导致所有三种细胞系中血清刺激的DNA合成的剂量和时间依赖性降低，IC 50在亚纳摩尔范围内。Ang-（1-7）受体拮抗剂[d-Ala（7）]-Ang-（1 -7）可阻断Ang-（1 -7）对血清刺激的SK-LU-1细胞DNA合成的抑制作用，而AT（1）和AT（2）血管紧张素受体亚型拮抗剂均不能阻断对七肽的反应。在3种肺癌细胞株中均检测到Ang-（1-7）受体MAS mRNA和蛋白，提示Ang-（1 - 7）的抗肿瘤增殖作用可能是通过非AT（1）、非AT（2）、AT（1-7））受体MAS介导的。其他血管紧张素肽[Ang I、Ang II、Ang-（2-8）、Ang-（3-8）和Ang-（3-7）]不减弱SK-LU-1细胞的促分裂原刺激的DNA合成，表明Ang-（1-7）选择性地抑制SK-LU-1癌细胞生长。用10 nM Ang-（1-7）预处理SK-LU-1细胞可减少血清刺激的细胞外信号调节激酶（ERK）1和ERK 2的磷酸化，表明抗增殖作用可能至少部分通过抑制ERK信号转导途径发生。这项研究的结果表明，Ang-（1-7）通过激活血管紧张素肽受体抑制肺癌细胞生长，并可能代表一种新的化疗和化学预防治疗肺癌。
Angiotensin-(1-7) [Ang-(1-7)] is an endogenous peptide hormone of the renin-angiotensin system with vasodilator and anti-proliferative properties. Human adenocarcinoma SK-LU-1 and A549 cells as well as non-small lung cancer SK-MES-1 cells were treated with serum in the presence and absence of Ang-(1-7), to determine whether Ang-(1-7) inhibits the growth of lung cancer cells. Ang-(1-7) caused a significant reduction in serum-stimulated growth in all three lung cancer cell lines. Treatment with Ang-(1-7) resulted in both a dose- and time-dependent reduction in serum-stimulated DNA synthesis in all three cell lines, with IC50's in the sub-nanomolar range. The Ang-(1-7) receptor antagonist [d-Ala(7)]-Ang-(1-7) blocked the attenuation of the serum-stimulated DNA synthesis of SK-LU-1 cells by Ang-(1-7), while neither AT(1) nor AT(2) angiotensin receptor subtype antagonists prevented the response to the heptapeptide. MAS mRNA and protein, a receptor for Ang-(1-7), was detected in the three lung cancer cell lines, suggesting that the anti-proliferative effect of Ang-(1-7) in the cancer cells may be mediated by the non-AT(1), non-AT(2), AT((1-7)) receptor MAS. Other angiotensin peptides [Ang I, Ang II, Ang-(2-8), Ang-(3-8) and Ang-(3-7)] did not attenuate mitogen-stimulated DNA synthesis of SK-LU-1 cells, demonstrating that Ang-(1-7) selectively inhibits SK-LU-1 cancer cell growth. Pre-treatment of SK-LU-1 cells with 10 nM Ang-(1-7) reduced serum-stimulated phosphorylation of extracellular signal-regulated kinase (ERK)1 and ERK2, indicating that the anti-proliferative effects may occur, at least in part, through inhibition of the ERK signal transduction pathway. The results of this study suggest that Ang-(1-7) inhibits lung cancer cell growth through the activation of an angiotensin peptide receptor and may represent a novel chemotherapeutic and chemopreventive treatment for lung cancer.