1. Academic Validation
  2. 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

  • J Exp Clin Cancer Res. 2020 Jun 23;39(1):119. doi: 10.1186/s13046-020-01621-y.
Ya Cao 1 2 Jinglong Wang 1 Hua Tian 3 Guo-Hui Fu 4
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 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.
  • 4 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.
Abstract

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.

Keywords

Apoptosis; CYT997; Gastric cancer; JAK2/STAT3; ROS.

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