Bisphosphonates suppress insulin-like growth factor 1-induced angiogenesis via the HIF-1alpha/VEGF signaling pathways in human breast cancer cells.
Bisphosphonates suppress insulin-like growth factor 1-induced angiogenesis via the HIF-1alpha/VEGF signaling pathways in human breast cancer cells.
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DOI：
10.1002/ijc.24710
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发表时间：
2010-01-01
影响因子：
6.4
通讯作者：
Le, Anh D.
中科院分区：
文献类型：
--
作者：
Tang, Xudong;Zhang, Qunzhou;Shi, Shihong;Yen, Yun;Li, Xiangyong;Zhang, Yuefei;Zhou, Keyuan;Le, Anh D.
据报道，双膦酸类的辅助化疗可以延缓乳腺癌的骨转移，提高患者的总体生存率。除了抗吸收作用外，双膦酸盐在体内和体外都表现出抗肿瘤活性，其机制包括抗血管生成。在这项研究中，我们研究了非含氮和含氮双膦酸盐氯屈膦酸盐和帕米膦酸盐在IGF-1反应性人乳腺癌细胞中抗血管生成作用的潜在分子机制。我们检测了双膦酸类化合物对在肿瘤血管生成中起关键作用的缺氧诱导因子-1α/血管内皮生长因子轴的影响，结果显示帕米膦酸盐和氯屈膦均显著抑制胰岛素样生长因子-1诱导的α蛋白积聚和血管内皮生长因子的表达。从机制上，我们发现帕米磷酸钠和氯屈磷酸钠对缺氧诱导因子-1α的表达没有影响，但明显促进了胰岛素样生长因子-1诱导的α蛋白的降解。同时，我们发现帕米磷酸钠和氯屈膦酸盐的存在导致蛋白酶体抑制后由胰岛素样生长因子-1诱导的乳腺癌细胞中新合成的缺氧诱导因子-1α蛋白呈剂量依赖性的下降，从而间接反映了蛋白质合成的抑制。此外，我们的结果表明，双膦酸类化合物对缺氧诱导因子-1AKT/α轴的抑制作用与抑制PI-3K/AKT/MTOR信号通路有关。我们一致地证明，帕米磷酸钠和氯屈磷酸钠在体外和体内都能有效地抑制IGF-1刺激的MCF-7细胞诱导的肿瘤血管生成。这些发现突显了双膦酸类药物抑制乳腺癌细胞肿瘤血管生成的一个重要机制。
Adjunctive chemotherapy with bisphosphonates has been reported to delay bone metastasis and improve overall survival in breast cancer. Aside from its anti-resorptive effect, bisphosphonates exhibit antitumor activities, in vitro and in vivo, via several mechanisms including anti-angiogenesis. In this study, we investigated the potential molecular mechanisms underlying the anti-angiogenic effect of non nitrogen-containing and nitrogen-containing bisphosphonates, clodronate and pamidronate, in IGF-1 responsive human breast cancer cells. We tested whether bisphosphonates had any effects on HIF-1α/VEGF axis that plays a pivotal role in tumor angiogenesis, and our results showed that both pamidronate and clodronate significantly suppressed IGF-1 induced HIF-1α protein accumulation and VEGF expression in MCF-7 cells. Mechanistically, we found that either pamidronate or clodronate did not affect mRNA expression of HIF-1α, but apparently promoted the degradation of IGF-1 induced HIF-1α protein. Meanwhile, we found that the presence of pamidronate and clodronate led to a dose-dependent decease in the newly-synthesized HIF-1α protein induced by IGF-1 in breast cancer cells after proteasomal inhibition, thus indirectly reflecting the inhibition of protein synthesis. In addition, our results indicated that the inhibitory effects of bisphosphonates on the HIF-1α/VEGF axis are associated with the inhibition of the PI-3K/AKT/mTOR signaling pathways. Consistently, we demonstrated that pamidronate and clodronate functionally abrogated both in vitro and in vivo tumor angiogenesis induced by IGF-1 stimulated MCF-7 cells. These findings have highlighted an important mechanism of the pharmacological action of bisphosphonates in the inhibition of tumor angiogenesis in breast cancer cells.
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影响因子：
3.5
作者：
Ferretti, G;Fabi, A;Cognetti, F
通讯作者：
Cognetti, F
影响因子：
8
作者：
Cascio, S.;Bartella, V.;Surmacz, E.
通讯作者：
Surmacz, E.
影响因子：
6
作者：
de Ostrovich, Krisztina Kovacs;Lambertz, Isabel;Fuchs-Young, Robin
通讯作者：
Fuchs-Young, Robin
影响因子：
4
作者：
Berven, LA;Crouch, MF
通讯作者：
Crouch, MF
影响因子：
3.8
作者：
Chen, Helen H. W.;Su, Wu-Chou;Lee, Wen-Ying
通讯作者：
Lee, Wen-Ying