Mitochondrial ROS accumulation inhibiting JAK2/STAT3 pathway is a critical modulator of CYT997-induced autophagy and apoptosis in gastric cancer
Mitochondrial ROS accumulation inhibiting JAK2/STAT3 pathway is a critical modulator of CYT997-induced autophagy and apoptosis in gastric cancer
复制标题
DOI：
10.1186/s13046-020-01621-y
复制
发表时间：
2020-06-23
影响因子：
11.3
通讯作者：
Fu, Guo-Hui
中科院分区：
文献类型：
--
作者：
Cao, Ya;Wang, Jinglong;Fu, Guo-Hui
背景胃癌（gastric cancer，GC）是世界范围内常见的恶性肿瘤之一，预后差。尽管近年来胃癌的治疗取得了很大进展，但胃癌患者的预后仍不理想，CYT 997是一种新型的微管靶向药物，近年来被认为是一种有前途的抗癌候选药物，但其在胃癌中的作用尚不清楚。方法采用CCK-8法和流式细胞术检测细胞增殖和凋亡。共聚焦显微镜和流式细胞仪检测线粒体活性氧的含量。采用胃癌患者来源的异种移植瘤（PDX）模型评价CYT 997的体内抗肿瘤活性。结果CYT 997抑制胃癌细胞增殖，诱导细胞凋亡，并引发自噬。CYT 997通过触发GC细胞内线粒体ROS的产生诱导细胞凋亡。活性氧清除剂N-乙酰半胱氨酸（NAC）和线粒体醌（MitoQ）可明显减弱CYT 997诱导的胃癌细胞G2/M期阻滞和凋亡。自噬抑制剂3-MA预处理促进了CYT 997诱导细胞凋亡的作用。CYT 997通过调节Janus激酶2（JAK 2）/信号转导子和转录激活子3（STAT 3）信号通路发挥作用。此外，CYT 997抑制胃癌患者来源的异种移植（PDX）肿瘤的生长。结论CYT 997通过激活线粒体ROS聚集，沉默JAK 2/STAT 3通路，诱导胃癌细胞自噬和凋亡。CYT 997有可能成为治疗胃癌的候选药物。
Background Gastric cancer (GC) is a common form of malignant cancer in worldwide which has a poor prognosis. Despite recent improvements in the treatment of GC, the prognosis is not yet satisfactory for GC patients.CYT997, a novel microtubule-targeting agent, recently has been identified to be a promising anticancer candidate for the treatment of cancers; however, the effects of CYT997 in GC remain largely unknown. Methods Cell proliferation and apoptosis were detected by CCK8 assay and flow cytometry. The mitochondrial ROS were detected by confocal microscope and flow cytometry. Gastric cancer patient-derived xenograft (PDX) model was used to evaluate its antitumor activity of CYT997 in vivo. Results CYT997 inhibited gastric cancer cell proliferation and induced cell apoptosis and triggered autophagy. CYT997 induced apoptosis through triggering intracellular mitochondrial ROS generation in GC cells. ROS scavengers N-acetylcysteine (NAC) and Mitoquinone (MitoQ) distinctly weakened CYT997-induced cell cycle G2/M arrest and apoptosis in GC cells. Pretreatment with autophagy inhibitor 3-MA promoted the effect of CYT997 on cells apoptosis. Mechanistically, CYT997 performed its function through regulation of Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway in GC cells. In addition, CYT997 inhibited growth of gastric cancer patient-derived xenograft(PDX) tumors. Conclusions CYT997 induces autophagy and apoptosis in gastric cancer by triggering mitochondrial ROS accumulation to silence JAK2/STAT3 pathway. CYT997 might be a potential antitumor drug candidate to treat GC.