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首页> 外文期刊>Journal of experimental & clinical cancer research : >Apatinib triggers autophagic and apoptotic cell death via VEGFR2/STAT3/PD-L1 and ROS/Nrf2/p62 signaling in lung cancer
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Apatinib triggers autophagic and apoptotic cell death via VEGFR2/STAT3/PD-L1 and ROS/Nrf2/p62 signaling in lung cancer

机译：apatinib通过VEGFR2 / Stat3 / PD-L1和ROS / NRF2 / P62信号传导在肺癌中触发自噬和凋亡细胞死亡

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Recently, a variety of clinical trials have shown that apatinib, a small-molecule anti-angiogenic drug, exerts promising inhibitory effects on multiple solid tumors, including non-small cell lung cancer (NSCLC). However, the underlying molecular mechanism of apatinib on NSCLC remains unclear. MTT, EdU, AO/EB staining, TUNEL staining, flow cytometry, colony formation assays were performed to investigate the effects of apatinib on cell proliferation, cell cycle distribution, apoptosis and cancer stem like properties. Wound healing and transwell assays were conducted to explore the role of apatinib on migration and invasion. The regulation of apatinib on VEGFR2/STAT3/PD-L1 and ROS/Nrf2/p62 signaling were detected. Furthermore, we collected conditioned medium (CM) from A549 and H1299 cells to stimulate phorbol myristate acetate (PMA)-activated THP-1 cells, and examined the effect of apatinib on PD-L1 expression in macrophages. The Jurkat T cells and NSCLC cells co-culture model was used to assess the effect of apatinib on T cells activation. Subcutaneous tumor formation models were established to evaluate the effects of apatinib in vivo. Histochemical, immunohistochemical staining and ELISA assay were used to examine the levels of signaling molecules in tumors. We showed that apatinib inhibited cell proliferation and promoted apoptosis in NSCLC cells in vitro. Apatinib induced cell cycle arrest at G1 phase and suppressed the expression of Cyclin D1 and CDK4. Moreover, apatinib upregulated Cleaved Caspase 3, Cleaved Caspase 9 and Bax, and downregulated Bcl-2 in NSCLC cells. The colony formation ability and the number of CD133 positive cells were significantly decreased by apatinib, suggesting that apatinib inhibited the malignant and stem-like features of NSCLC cells. Mechanistically, apatinib inhibited PD-L1 and c-Myc expression by targeting VEGFR2/STAT3 signaling. Apatinib also inhibited PD-L1 expression in THP-1 derived macrophages stimulated by CM from NSCLC cells. Furthermore, apatinib pretreatment increased CD69 expression and IFN-γ secretion in stimulated Jurkat T cells co-cultured with NSCLC cells. Apatinib also promoted ROS production and inhibited Nrf2 and p62 expression, leading to the autophagic and apoptotic cell death in NSCLC. Moreover, apatinib significantly inhibited tumor growth in vivo. Our data indicated that apatinib induced autophagy and apoptosis in NSCLC via regulating VEGFR2/STAT3/PD-L1 and ROS/Nrf2/p62 signaling.
机译：最近，各种临床试验表明，一种小分子抗血管生成药物的阿凡替尼对多种实体肿瘤产生了有希望的抑制作用，包括非小细胞肺癌（NSCLC）。然而，Apatinib上的NSCLC的底层分子机制仍不清楚。进行MTT，EDU，AO / EB染色，TUNEL染色，流式细胞术，菌落形成测定以研究磷钛对细胞增殖，细胞循环分布，细胞凋亡和癌症的影响。进行伤口愈合和转发测定以探讨磷钛对迁移和侵袭的作用。检测到在VEGFR2 / Stat3 / PD-L1和ROS / NRF2 / P62信号传导上的调节。此外，我们从A549和H1299细胞收集条件培养基（CM），以刺激Phorbol Myristerate醋酸酯（PMA） - 活化的THP-1细胞，并检查了磷钛对巨噬细胞PD-L1表达的影响。 Jurkat T细胞和NSCLC细胞共培养模型用于评估磷钛对T细胞活化的影响。建立了皮下肿瘤形成模型，以评估磷钛在体内的作用。组织化学，免疫组织化学染色和ELISA测定用于检查肿瘤中的信号分子水平。我们表明，阿凡尼在体外抑制细胞增殖和促进了NSCLC细胞的细胞凋亡。 Apatinib诱导G1相的细胞周期停滞，并抑制了细胞周期蛋白D1和CDK4的表达。此外，Apatinib上调切割的胱天悬蛋酶3，切割的胱天蛋白酶9和Bax和NSCLC细胞中的下调Bcl-2。亚辛尼显着降低了菌落形成能力和CD133阳性细胞的数量，表明阿凡替尼抑制了NSCLC细胞的恶性和干燥的特征。通过靶向VEGFR2 / STAT3信号传导，机械地，apatinib抑制PD-L1和C-MYC表达。 Apatinib还抑制来自来自NMSCLC细胞刺激的THP-1衍生巨噬细胞中的PD-L1表达。此外，Apatinib预处理增加了用NSCLC细胞共培养的刺激的Jurkat T细胞中的CD69表达和IFN-γ分泌。 Apatinib还促进了ROS生产和抑制NRF2和P62表达，导致NSCLC中的自噬和凋亡细胞死亡。此外，磷钛显着抑制体内肿瘤生长。我们的数据表明，Apatinib通过调节VEGFR2 / Stat3 / PD-L1和ROS / NRF2 / P62信号传导诱导NSCLC中的自噬和凋亡。

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