CX-5461 induces autophagy and inhibits tumor growth via mammalian target of rapamycin-related signaling pathways in osteosarcoma.
CX-5461 induces autophagy and inhibits tumor growth via mammalian target of rapamycin-related signaling pathways in osteosarcoma.
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CX-5461 通过骨肉瘤中雷帕霉素相关信号通路的哺乳动物靶标诱导自噬并抑制肿瘤生长
DOI：
10.2147/ott.s104513
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发表时间：
2016
影响因子：
4
通讯作者：
Li X
中科院分区：
文献类型：
--
作者：
Li L;Li Y;Zhao J;Fan S;Wang L;Li X
骨肉瘤（OS）是最常见的原发性骨肿瘤，但该疾病的分子机制尚未得到很好的理解，转移性OS的治疗仍然是一个挑战。癌症中快速的核糖体RNA合成是由RNA聚合酶I转录的，这导致细胞无节制的生长。最近发现的CX-5461是一种选择性RNA聚合酶I抑制剂，具有抑制核糖体RNA合成和抗增殖的作用。在这里，我们证明，CX-5461诱导G2期阻滞的细胞周期和微管相关蛋白1轻链3 II亚型的表达在OS细胞系。电镜下可观察到自噬空泡，3-甲基腺嘌呤可阻止CX-5461介导的细胞死亡。此外，它显着增加磷酸化AMP激活蛋白激酶α（p-AMPK α）。（Thr 172）表达和MNNG细胞中p-Akt（Ser 473）表达的降低，这抑制了它们的下游效应物，雷帕霉素的哺乳动物靶标。另一方面，CX-5461增加了U2-OS细胞中p53的积累及其靶基因p21、MDM 2和Sestrin 1/2的信使RNA水平。p53表达的敲低显著损害CX-5461诱导的细胞死亡以及轻链3-II和p21的表达。它还显着增强阿霉素介导的细胞毒性作用，在体外和体内与加性表达的p53，p21，和轻链3-II在U2-OS细胞。我们的数据表明，CX-5461可能通过依赖于p53状态的雷帕霉素相关信号通路的哺乳动物靶点诱导自噬，并发挥p53依赖的协同抗肿瘤作用。这些结果表明，CX-5461可能是有希望的OS的临床治疗，特别是携带野生型p53的病例。
Osteosarcoma (OS) is the most common primary bone tumor, but molecular mechanisms of the disease have not been well understood, and treatment of metastatic OS remains a challenge. Rapid ribosomal RNA synthesis in cancer is transcribed by RNA polymerase I, which results in unbridled cell growth. The recent discovery of CX-5461, a selective RNA polymerase I inhibitor, exerted its inhibitory effect of ribosomal RNA synthesis and antiproliferative potency. Here, we demonstrate that CX-5461 induces G2 arrest in the cell cycle and expression of microtubule-associated protein 1 light chain 3 II isoform in OS cell lines. Autophagic vacuoles could be observed in electron microscopy and 3-methyladenine prevented cell death mediated by CX-5461. Moreover, it significantly augmented phosphorylated AMP-Activated Protein Kinases α (p-AMPK α). (Thr172) expression in U2-OS cells and decreased p-Akt (Ser473) expression in MNNG cells, respectively, which repressed their downstream effector, mammalian target of rapamycin. On the other hand, CX-5461 increased p53 accumulation and messenger RNA level of its target genes, p21, MDM2, and Sestrin1/2 in U2-OS cells. Knockdown of p53 expression markedly impaired cell death as well as the expression of light chain 3-II and p21 induced by CX-5461. It also significantly enhanced doxorubicin-mediated cytotoxic effect in vitro and in vivo together with additive expression of p53, p21, and light chain 3-II in U2-OS cells. Our data indicate that CX-5461 might induce autophagy via mammalian target of rapamycin-associated signaling pathways dependent on p53 status and exert p53-dependent synergistic antitumor effect combined with doxorubicin in OS. These results suggest that CX-5461 might be promising in clinical therapy for OS, especially cases harboring wild-type p53.