Apatinib induces apoptosis and autophagy via the PI3K/AKT/mTOR and MAPK/ERK signaling pathways in neuroblastoma
Apatinib induces apoptosis and autophagy via the PI3K/AKT/mTOR and MAPK/ERK signaling pathways in neuroblastoma
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DOI：
10.3892/ol.2020.11913
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发表时间：
2020-07
期刊：
影响因子：
2.9
通讯作者：
Xiying Yu;H. Fan;Xingran Jiang;Wei Zheng;Yanan Yang;M. Jin;Xiao-li Ma;Wei-Wei Jiang-Wei
中科院分区：
文献类型：
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作者：
Xiying Yu;H. Fan;Xingran Jiang;Wei Zheng;Yanan Yang;M. Jin;Xiao-li Ma;Wei-Wei Jiang-Wei
在过去的30年里，神经母细胞瘤(NB)对于局限性疾病的患者的临床预后有了显著的改善，但转移患者的总体生存率(OS)仍然很低。阿帕替尼是血管内皮生长因子受体-2(VEGFR-2)酪氨酸激酶的选择性抑制剂，被发现与肿瘤转移高度相关，已被报道在多种类型的癌症中发挥抗肿瘤作用。然而，阿帕替尼对NB的作用仍相对未知。本研究旨在探讨阿帕替尼对体外培养的NB细胞的抗肿瘤作用。结果表明，阿帕替尼抑制细胞活力和集落形成，诱导细胞周期停滞和细胞凋亡。此外，阿帕替尼除了促进NB细胞的自噬外，还抑制了NB细胞的迁移和侵袭。Western blotting显示，经阿帕替尼处理后，细胞内磷酸化(P)-AKT、p-mTOR和p-p70S6K及其下游与细胞周期和细胞凋亡相关的分子如细胞周期蛋白d1和bcl2/bax比值均显著降低。此外，Western blotting和免疫荧光分析表明，经阿帕替尼处理后，在自噬体内表达的微管相关蛋白1A/1B-轻链3-II的表达水平上调。综上所述，本研究结果提示阿帕替尼可能通过PI3K/AKT/mTOR和丝裂原活化蛋白激酶/ERK信号通路诱导NB细胞的凋亡和自噬。因此，阿帕替尼可能是一种潜在的抗肿瘤药物，用于临床治疗NB。
The clinical outcome of neuroblastoma (NB) has significantly improved in the last 30 years for patients with localized disease; however, the overall survival (OS) for patients with metastasis remains poor. Apatinib, a selective inhibitor of the vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase, which was discovered to be highly associated with metastasis, has been reported to exert antitumor effects in numerous types of cancer. However, the effect of apatinib in NB remains relatively unknown. The present study aimed to investigate the antitumor effects of apatinib in NB cells in vitro. The results revealed that apatinib inhibited cell viability and colony formation, whilst inducing cell cycle arrest and the apoptosis of NB cells. Additionally, apatinib inhibited the migration and invasion of NB cells, in addition to promoting the autophagy of NB cells. Western blotting demonstrated that the protein expression levels of phosphorylated (p)-AKT, p-mTOR and p-P70S6K, and downstream molecules associated with the cell cycle and apoptosis, such as cyclin D1 and the Bcl-2/Bax ratio of NB cells, were significantly decreased following treatment with apatinib. In addition, western blotting and immunofluorescence assays identified that the expression level of microtubule-associated protein 1A/1B-light chain 3-II, which is expressed in autophagosomes, was upregulated following apatinib treatment. In conclusion, the findings of the present study suggested that apatinib may induce apoptosis and autophagy via the PI3K/AKT/mTOR and mitogen-activated protein kinase/ERK signaling pathways in NB cells. Thus, apatinib may be a potential antitumor agent for the clinical treatment of NB.