唑来膦酸通过 Erk1/2 和 Akt 通路抑制宫颈癌肿瘤干细胞的干性表型，并诱导其凋亡和细胞周期停滞，从而抑制其生长。
Zoledronic acid inhibits the growth of cancer stem cell derived from cervical cancer cell by attenuating their stemness phenotype and inducing apoptosis and cell cycle arrest through the Erk1/2 and Akt pathways.
机构信息
Lung Cancer Center, Laboratory of Lung Cancer, West China Hospital of Sichuan University, Chengdu, 610041, Sichuan, China.
Department of Medical Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, 610041, Sichuan, China.
出版信息
J Exp Clin Cancer Res. 2019 Feb 21;38(1):93. doi: 10.1186/s13046-019-1109-z.
BACKGROUND
Zoledronic acid is the most potent osteoclast inhibitor and is widely used for advanced cancer patients with bone metastasis, but its role on cancer stem cells (CSCs) remains unclear. In the present study, we aimed to identify the stemness phenotypic characteristics of CSCs derived from cervical cancer cells and explore the anti-cancer efficiency of zoledronic acid on these cells, as well as the possible molecular mechanisms.
METHODS
Stemness phenotypic identification of cervical cancer cells derived CSCs was performed via sphere formation efficiency (SFE), tumorigenesis, immunofluorescence staining, Transwell assay, and western blot. Anti-cancer efficiency of zoledronic acid on these cells (including proliferation, stemness phenotype, apoptosis, and cell cycle) was carried out through MTT assay, SFE, transwell, DAPI staining, flow cytometry, immunofluorescence, TUNEL staining, and western blot, both in vitro and in vivo.
RESULTS
Enhanced self-renewal ability, including SFE and tumorigenesis, was verified in cervical cancer cells derived CSCs compared to parental cervical cancer cells. Specifically, the expression of ALDH1, Sox2, CD49f, Nanog, and Oct4 was significantly up-regulated in cervical cancer cells derived CSCs. Furthermore, enhanced migratory ability was observed in these cells along with up-regulated N-cadherin and Vimentin and down-regulated E-cadherin. Zoledronic acid inhibited cervical cancer cells derived CSCs proliferation in vitro and in vivo. The stemness phenotype of these CSCs including tumor sphere formation, migration, as well as the expression of the aforementioned associated markers was also suppressed. In addition, zoledronic acid significantly induced apoptosis and cell cycle arrest of cervical cancer cells derived CSCs in a dose-dependent manner. Mechanistically, the expression of phosphorylated Erk1/2 and Akt was significantly increased in cervical cancer cells derived CSCs compared to parental cervical cancer cells. Zoledronic acid inhibited phosphorylated Erk1/2 and Akt in cervical cancer cells derived CSCs. IGF-1, a potent stimulator for Erk1/2 and PI3K/Akt, attenuated the aforementioned anti-cancer effect of zoledronic acid.
CONCLUSIONS
Zoledronic acid inhibited the growth of cervical cancer cells derived CSCs through attenuating their stemness phenotype, inducing apoptosis, and arresting cell cycle. The suppression of phosphorylated Erk1/2 and Akt was involved in this process.
背景
唑来膦酸是最强的破骨细胞抑制剂，广泛用于治疗有骨转移的晚期癌症患者，但它对癌症干细胞（CSC）的作用仍不清楚。本研究旨在鉴定来源于宫颈癌的 CSC 的干细胞表型特征，并探讨唑来膦酸对这些细胞的抗癌效率及其可能的分子机制。
方法
通过球体形成效率（SFE）、肿瘤发生、免疫荧光染色、Transwell 检测和 Western blot 鉴定来源于宫颈癌的 CSC 的干细胞表型特征。通过 MTT 检测、SFE、Transwell、DAPI 染色、流式细胞术、免疫荧光、TUNEL 染色和 Western blot 检测，研究唑来膦酸对这些细胞（包括增殖、干细胞表型、凋亡和细胞周期）的抗癌效率，包括在体内外。
结果
来源于宫颈癌的 CSC 较亲本宫颈癌细胞具有更强的自我更新能力，包括 SFE 和肿瘤发生。具体而言，ALDH1、Sox2、CD49f、Nanog 和 Oct4 的表达在来源于宫颈癌的 CSC 中显著上调。此外，这些细胞的迁移能力增强，同时 N-cadherin 和 Vimentin 上调，E-cadherin 下调。唑来膦酸抑制来源于宫颈癌的 CSCs 的体外和体内增殖。这些 CSCs 的干细胞表型，包括肿瘤球体形成、迁移以及上述相关标志物的表达，也受到抑制。此外，唑来膦酸以剂量依赖性方式显著诱导来源于宫颈癌的 CSCs 的凋亡和细胞周期停滞。机制上，来源于宫颈癌的 CSC 中磷酸化 Erk1/2 和 Akt 的表达明显高于亲本宫颈癌细胞。唑来膦酸抑制来源于宫颈癌的 CSCs 中磷酸化 Erk1/2 和 Akt。IGF-1 是 Erk1/2 和 PI3K/Akt 的有效刺激物，可减弱唑来膦酸的上述抗癌作用。
结论
唑来膦酸通过抑制其干细胞表型、诱导凋亡和阻止细胞周期来抑制来源于宫颈癌的 CSCs 的生长。抑制磷酸化 Erk1/2 和 Akt 参与了这一过程。
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