Apatinib, a novel vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase inhibitor, has been approved for the treatment of metastatic gastric cancer and other tumors. Apatinib exerts antiproliferative and proapoptotic effects in different kinds of cancer cells. However, the molecular mechanisms by which apatinib effective against esophageal squamous cell carcinoma (ESCC) have only been partially researched and whether it has a sensitizing effect on paclitaxel remains unclear. The effects of apatinib or paclitaxel on endoplasmic reticulum (ER) stress, autophagy, apoptosis and proliferation of ESCC cell lines were evaluated. Western blot and immunohistochemistry analyses were performed to detect the expression of related genes. The weight and volume of xenograft tumors in mice were measured. In the current study, we elucidated the antiproliferative and ER-stress-mediated autophagy-inducing effects of apatinib on ECA-109 and KYSE-150 esophageal squamous cancer cells and identified the underlying mechanisms of its action. We demonstrated that apatinib not only inhibited the proliferation and induced the apoptosis of ESCC cells, but also activated ER stress and triggered protective autophagy. Moreover, inhibiting autophagy by chloroquine (CQ) enhanced the apatinib-induced apoptosis of ESCC cells through the IRE-1α–AKT–mTOR pathway. In addition, we showed, for the first time, the paclitaxel combined with apatinib and CQ exhibited the best antitumor effect on ESCC both in vivo and in vitro via the IRE-1α–AKT–mTOR pathway. Our data showed that apatinib induced ER stress, autophagy and apoptosis in ESCC. Inhibiting autophagy by CQ enhanced apatinib-induced apoptosis. The combination of apatinib and CQ sensitized ESCC cells to paclitaxel to induce apoptosis through the IRE-1α–AKT–mTOR signaling pathway, thus providing the basis for its use in innovative anticancer therapeutic strategies.

中文翻译：

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阿帕替尼通过 IRE-1α-AKT-mTOR 通路在食管鳞状细胞癌中诱导内质网应激介导的细胞凋亡和自噬，并增强细胞对紫杉醇的敏感性

阿帕替尼是一种新型血管内皮生长因子受体-2 (VEGFR-2) 酪氨酸激酶抑制剂，已被批准用于治疗转移性胃癌和其他肿瘤。阿帕替尼在不同种类的癌细胞中发挥抗增殖和促凋亡作用。然而，阿帕替尼对食管鳞状细胞癌（ESCC）有效的分子机制仅被部分研究，其是否对紫杉醇具有致敏作用尚不清楚。评估了阿帕替尼或紫杉醇对 ESCC 细胞系的内质网 (ER) 应激、自噬、凋亡和增殖的影响。进行蛋白质印迹和免疫组织化学分析以检测相关基因的表达。测量小鼠异种移植肿瘤的重量和体积。在目前的研究中，我们阐明了阿帕替尼对 ECA-109 和 KYSE-150 食管鳞癌细胞的抗增殖和内质网应激介导的自噬诱导作用，并确定了其作用的潜在机制。我们证明了阿帕替尼不仅抑制了 ESCC 细胞的增殖并诱导了细胞凋亡，而且还激活了内质网应激并触发了保护性自噬。此外，氯喹（CQ）抑制自噬可通过 IRE-1α-AKT-mTOR 通路增强阿帕替尼诱导的 ESCC 细胞凋亡。此外，我们首次表明紫杉醇联合阿帕替尼和 CQ 通过 IRE-1α-AKT-mTOR 通路在体内和体外对 ESCC 表现出最佳的抗肿瘤作用。我们的数据显示，阿帕替尼在 ESCC 中诱导内质网应激、自噬和细胞凋亡。通过 CQ 抑制自噬增强了阿帕替尼诱导的细胞凋亡。阿帕替尼和 CQ 的组合使 ESCC 细胞对紫杉醇敏感，从而通过 IRE-1α-AKT-mTOR 信号通路诱导细胞凋亡，从而为其在创新的抗癌治疗策略中的应用提供了基础。