Synergistic Autophagy Effect of miR-212-3p in Zoledronic Acid-Treated In Vitro and Orthotopic In Vivo Models and in Patient-Derived Osteosarcoma Cells
Synergistic Autophagy Effect of miR-212-3p in Zoledronic Acid-Treated In Vitro and Orthotopic In Vivo Models and in Patient-Derived Osteosarcoma Cells
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DOI：
10.3390/cancers11111812
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发表时间：
2019-11-01
期刊：
影响因子：
5.2
通讯作者：
Kong, Chang-Bae
中科院分区：
文献类型：
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作者：
Oh, Ju Yeon;Kim, Eun Ho;Kong, Chang-Bae
骨肉瘤（OS）起源于骨样骨组织，容易发生转移，死亡率较高。尽管有多种治疗 OS 的方法，但对于大多数晚期 OS 患者来说，尚不存在有效的治愈方法。唑来膦酸（ZOL）是第三代双膦酸盐，可抑制破骨细胞介导的骨吸收，并在治疗各种类型实体瘤患者的骨转移方面显示出疗效。在这里，我们试图阐明 ZOL 抑制 OS 细胞增殖的机制。 ZOL 处理抑制 OS 细胞增殖、活力和集落形成。通过 RNA 干扰 Beclin-1 或 ATG5 抑制自噬可抑制 ZOL 诱导的 OS 细胞死亡。 ZOL 通过抑制 OS 细胞系和患者来源的 OS 细胞中雷帕霉素/p70S6 激酶途径的蛋白激酶 B/哺乳动物靶标以及细胞外信号调节激酶信号依赖性自噬来诱导自噬。 miRNA 微阵列显示 ZOL 增加了 miR-212-3p 的水平，已知 miR-212-3p 在自噬、OS 体外和体内系统中发挥重要作用。总的来说，我们的数据提供了通过 ZOL 治疗增加 miR-212-3p 如何协同诱导 OS 细胞自噬的机制见解，为 ZOL + miR-212-3p 在治疗 OS 中进行大规模临床评估提供了临床前基本原理。
Osteosarcoma (OS) originates from osteoid bone tissues and is prone to metastasis, resulting in a high mortality rate. Although several treatments are available for OS, an effective cure does not exist for most patients with advanced OS. Zoledronic acid (ZOL) is a third-generation bisphosphonate that inhibits osteoclast-mediated bone resorption and has shown efficacy in treating bone metastases in patients with various types of solid tumors. Here, we sought to clarify the mechanisms through which ZOL inhibits OS cell proliferation. ZOL treatment inhibited OS cell proliferation, viability, and colony formation. Autophagy inhibition by RNA interference against Beclin-1 or ATG5 inhibited ZOL-induced OS cell death. ZOL induced autophagy by repressing the protein kinase B/mammalian target of rapamycin/p70S6 kinase pathway and extracellular signal-regulated kinase signaling-dependent autophagy in OS cell lines and patient-derived OS cells. Microarrays of miRNA showed that ZOL increased the levels of miR-212-3p, which is known to play an important role in autophagy, in OS in vitro and in vivo systems. Collectively, our data provided mechanistic insight into how increased miR-212-3p through ZOL treatment induces autophagy synergistically in OS cells, providing a preclinical rationale for conducting a broad-scale clinical evaluation of ZOL + miR-212-3p in treating OS.