Mitochondrial ROS accumulation inhibiting JAK2/STAT3 pathway is a critical modulator of CYT997-induced autophagy and apoptosis in gastric cancer

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.