Yu Xiying, Fan Hongjun, Jiang Xingran, Zheng Wei, Yang Yanan, Jin Mei, Ma Xiaoli, Jiang Wei
Department of Etiology and Carcinogenesis and State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China.
Beijing Key Laboratory for Carcinogenesis and Cancer Prevention, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China.
Oncol Lett. 2020 Oct;20(4):52. doi: 10.3892/ol.2020.11913. Epub 2020 Jul 27.
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 . 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.
在过去30年中，局限性神经母细胞瘤（NB）患者的临床结局有了显著改善；然而，转移性患者的总生存期（OS）仍然较差。阿帕替尼是一种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，已发现其与转移高度相关，据报道在多种癌症类型中具有抗肿瘤作用。然而，阿帕替尼在NB中的作用仍相对未知。本研究旨在探讨阿帕替尼对NB细胞的抗肿瘤作用。结果显示，阿帕替尼抑制细胞活力和集落形成，同时诱导NB细胞的细胞周期停滞和凋亡。此外，阿帕替尼除了促进NB细胞的自噬外，还抑制NB细胞的迁移和侵袭。蛋白质印迹法表明，用阿帕替尼处理后，NB细胞中磷酸化（p）-AKT、p-mTOR和p-P70S6K的蛋白表达水平以及与细胞周期和凋亡相关的下游分子，如细胞周期蛋白D1和Bcl-2/Bax比值，均显著降低。此外，蛋白质印迹法和免疫荧光分析确定，在自噬体中表达的微管相关蛋白1A/1B轻链3-II的表达水平在阿帕替尼处理后上调。总之，本研究结果表明，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细胞凋亡和自噬。因此，阿帕替尼可能是NB临床治疗的一种潜在抗肿瘤药物。
