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

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.

Acetone Extract of Cornus officinalis Leaves Exerts Anti-Melanoma Effects via Inhibiting STAT3 Signaling

“… 33 In addition, several papers proved that the anti-cancer strategy that triggers ROS generation in cancer cells to induce apoptosis is indeed feasible. 31 , 34–36 According to the present study, apoptosis and the production of ROS in tumor tissues were promoted by SZYY ( Figure 2A and B ), which suggests the increased level of oxidative stress in tumor tissue and the resulting apoptosis/death of tumor cells may also be one of the main mechanisms underlying the anti-melanoma effects of SZYY.…”

Mitochondrial Dynamics, ROS, and Cell Signaling: A Blended Overview

“…On the contrary, ERK, which is activated by growth factors, is considered pro-survival and oncogenic, and it antagonizes apoptosis by phosphorylating proapoptotic Bax and antiapoptotic Bcl-2 proteins, inhibiting and promoting their functions, respectively ( Figure 2 ) [ 87 ]. Activated ROS production also plays a role in JAK2/STAT3 signaling suppression and subsequent apoptosis induction; for example, Cao et al demonstrated that CYT997, a novel synthetic microtubule-disrupting agent, through the upregulation of mitochondrial ROS, triggers protective autophagy and inhibits the JAK2/STAT3 pathway, inducing gap 2 (G2)/mitosis (M) arrest and apoptosis in gastric cancer cells [ 88 ].…”

Oxidative Stress Activated by Sorafenib Alters the Temozolomide Sensitivity of Human Glioma Cells Through Autophagy and JAK2/STAT3-AIF Axis

“…Meanwhile, we inhibited the activation of JAK2 with the JAK2 inhibitor AG490 and found that AG490 significantly decreased the levels of phosphorylated JAK2 and STAT3 in U251 cells treated with the combination of sorafenib and TMZ ( Figure 7B and Supplementary Figure 7B ). Previous reports have revealed that ROS are involved in the JAK2/STAT3 pathway ( Cao et al, 2020 ); thus, we examined the effect of ROS on the JAK2/STAT3 pathway. As shown in Figure 7D , intracellular ROS were overproduced in U251 cells treated with the combination of sorafenib and TMZ compared with cells treated with either single agent alone.…”