PMID- 32576206 OWN - NLM STAT- MEDLINE DCOM- 20210305 LR - 20210305 IS - 1756-9966 (Electronic) IS - 0392-9078 (Print) IS - 0392-9078 (Linking) VI - 39 IP - 1 DP - 2020 Jun 23 TI - Mitochondrial ROS accumulation inhibiting JAK2/STAT3 pathway is a critical modulator of CYT997-induced autophagy and apoptosis in gastric cancer. PG - 119 LID - 10.1186/s13046-020-01621-y [doi] LID - 119 AB - 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. FAU - Cao, Ya AU - Cao Y AD - Pathology Center, Shanghai General Hospital/Faculty of Basic Medicine, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Institutes of Medical Sciences, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 280, South Chong-Qing Road, Shanghai, 200025, China. AD - State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, 25/Ln 2200, Xietu Road, Shanghai, 200032, China. FAU - Wang, Jinglong AU - Wang J AD - Pathology Center, Shanghai General Hospital/Faculty of Basic Medicine, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Institutes of Medical Sciences, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 280, South Chong-Qing Road, Shanghai, 200025, China. FAU - Tian, Hua AU - Tian H AD - State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, 25/Ln 2200, Xietu Road, Shanghai, 200032, China. htian@shsci.org. FAU - Fu, Guo-Hui AU - Fu GH AD - Pathology Center, Shanghai General Hospital/Faculty of Basic Medicine, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Institutes of Medical Sciences, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 280, South Chong-Qing Road, Shanghai, 200025, China. fuguhu@263.net. LA - eng GR - 81972581, 81472570/National Natural Science Foundation of China/ GR - shslczdzk01303/Shanghai Municipal Key Clinical Specialty/ GR - 19ZR1452800/Natural Science Foundation of Shanghai/ GR - 201940429/Foundation of Shanghai Municipal Health Commission/ PT - Journal Article DEP - 20200623 PL - England TA - J Exp Clin Cancer Res JT - Journal of experimental & clinical cancer research : CR JID - 8308647 RN - 0 (Biomarkers, Tumor) RN - 0 (CYT997) RN - 0 (Pyridines) RN - 0 (Pyrimidines) RN - 0 (Reactive Oxygen Species) RN - 0 (STAT3 Transcription Factor) RN - 0 (STAT3 protein, human) RN - EC 2.7.10.2 (JAK2 protein, human) RN - EC 2.7.10.2 (Janus Kinase 2) SB - IM MH - Animals MH - *Apoptosis MH - *Autophagy MH - Biomarkers, Tumor/genetics/metabolism MH - Cell Movement MH - Cell Proliferation MH - Female MH - G2 Phase Cell Cycle Checkpoints MH - Gene Expression Regulation, Neoplastic MH - Humans MH - Janus Kinase 2/genetics/*metabolism MH - Male MH - Membrane Potential, Mitochondrial MH - Mice MH - Mice, Inbred BALB C MH - Mice, Nude MH - Middle Aged MH - Mitochondria/drug effects/metabolism/*pathology MH - Neoplasm Invasiveness MH - Pyridines/*pharmacology MH - Pyrimidines/*pharmacology MH - Reactive Oxygen Species/*metabolism MH - STAT3 Transcription Factor/genetics/*metabolism MH - Signal Transduction MH - Stomach Neoplasms/drug therapy/genetics/metabolism/*pathology MH - Tumor Cells, Cultured MH - Xenograft Model Antitumor Assays PMC - PMC7310559 OTO - NOTNLM OT - Apoptosis OT - CYT997 OT - Gastric cancer OT - JAK2/STAT3 OT - ROS COIS- The authors declare that they have no competing interests. EDAT- 2020/06/25 06:00 MHDA- 2021/03/06 06:00 PMCR- 2020/06/23 CRDT- 2020/06/25 06:00 PHST- 2020/02/01 00:00 [received] PHST- 2020/06/10 00:00 [accepted] PHST- 2020/06/25 06:00 [entrez] PHST- 2020/06/25 06:00 [pubmed] PHST- 2021/03/06 06:00 [medline] PHST- 2020/06/23 00:00 [pmc-release] AID - 10.1186/s13046-020-01621-y [pii] AID - 1621 [pii] AID - 10.1186/s13046-020-01621-y [doi] PST - epublish SO - J Exp Clin Cancer Res. 2020 Jun 23;39(1):119. doi: 10.1186/s13046-020-01621-y.