Medical Department of Breast Oncology, The Third Affiliated Hospital of Harbin Medical University, Harbin, China.
J Cell Physiol. 2010 Oct;225(1):168-73. doi: 10.1002/jcp.22209.
Angiotensin II (Ang II) is a bioactive peptide of the renin-angiotensin system, acting not only as a vasoconstrictor but also as a growth promoter via angiotensin II type 1 receptor (AT1R) in some cancer. In this study, we examined the mechanisms by which Ang II affected the cell proliferation in AT1R-positive MCF-7 human breast cancer cells. Ang II stimulated the growth of breast cancer cells in a dose- and time-dependent manner. The maximal proliferation effect on MCF-7 cells was obtained with 10(-4) M Ang II at 24 h. Losartan (10(-5) M, an AT1R antagonist) significantly decreased the level of Ang-II-induced proliferative effects, whereas PD123319 (10(-5) M, an AT2R antagonist) had no effects. Moreover, Ang II could significantly accelerate S-phase progression, which was inhibited by losartan (10(-5) M) or LY294002 (50 microM, a PI3-kinase inhibitor). In addition, Ang II caused rapid activation of p-Akt in a dose- and time-dependent manner. 10(-4) M Ang II induced a significant increase of p-Akt in 15 min. The peak level of p-Akt could be persisted for at least 6 h. Among the signaling molecules downstream of Akt, we revealed that Ang II also significantly upregulated CyclinD1, GSK3beta, and downregulated p27. Pretreatment with losartan (10(-5) M) or LY294002 (50 microM) could significantly suppress these effects of Ang II. These findings suggest that Ang II plays a role in the growth of AT1R-positive breast cancer cells through PI3-kinase/Akt pathway activation. Therefore, targeting Ang II/AT1R signaling could be a novel therapeutic for breast cancer.
血管紧张素 II（Ang II）是肾素-血管紧张素系统的生物活性肽，不仅作为血管收缩剂，而且通过某些癌症中的血管紧张素 II 型 1 受体（AT1R）作为生长促进剂发挥作用。在这项研究中，我们研究了 Ang II 影响 AT1R 阳性 MCF-7 人乳腺癌细胞增殖的机制。Ang II 以剂量和时间依赖的方式刺激乳腺癌细胞的生长。用 10（-4）M Ang II 在 24 h 获得对 MCF-7 细胞的最大增殖作用。Losartan（10（-5）M，AT1R 拮抗剂）显着降低 Ang-II 诱导的增殖作用水平，而 PD123319（10（-5）M，AT2R 拮抗剂）则没有影响。此外，Ang II 可以显着加速 S 期进程，而 losartan（10（-5）M）或 LY294002（50 μM，PI3-激酶抑制剂）则抑制该进程。此外，Ang II 以剂量和时间依赖的方式快速激活 p-Akt。10（-4）M Ang II 在 15 分钟内诱导 p-Akt 显着增加。p-Akt 的峰值水平至少可维持 6 小时。在 Akt 下游的信号分子中，我们发现 Ang II 还显着上调了 CyclinD1、GSK3beta，并下调了 p27。用 losartan（10（-5）M）或 LY294002（50 μM）预处理可以显着抑制 Ang II 的这些作用。这些发现表明 Ang II 通过 PI3-激酶/Akt 途径的激活在 AT1R 阳性乳腺癌细胞的生长中起作用。因此，靶向 Ang II/AT1R 信号可能是治疗乳腺癌的一种新方法。
