Chaetocin-induced ROS-mediated apoptosis involves ATM–YAP1 axis and JNK-dependent inhibition of glucose metabolism

Abstract

Oxidative stress serves as an important regulator of both apoptosis and metabolic reprogramming in tumor cells. Chaetocin, a histone methyltransferase inhibitor, is known to induce ROS generation. As elevating basal ROS level sensitizes glioma cells to apoptosis, the ability of Chaetocin in regulating apoptotic and metabolic adaptive responses in glioma was investigated. Chaetocin induced glioma cell apoptosis in a ROS-dependent manner. Increased intracellular ROS induced (i) Yes-associated protein 1 (YAP1) expression independent of the canonical Hippo pathway as well as (ii) ATM and JNK activation. Increased interaction of YAP1 with p73 and p300 induced apoptosis in an ATM-dependent manner. Chaetocin induced JNK modulated several metabolic parameters like glucose uptake, lactate production, ATP generation, and activity of glycolytic enzymes hexokinase and pyruvate kinase. However, JNK had no effect on ATM or YAP1 expression. Coherent with the in vitro findings, Chaetocin reduced tumor burden in heterotypic xenograft glioma mouse model. Chaetocin-treated tumors exhibited heightened ROS, pATM, YAP1 and pJNK levels. Our study highlights the coordinated control of glioma cell proliferation and metabolism by ROS through (i) ATM-YAP1-driven apoptotic pathway and (ii) JNK-regulated metabolic adaptation. The elucidation of these newfound connections and the roles played by ROS to simultaneously shift metabolic program and induce apoptosis could provide insights toward the development of new anti-glioma strategies.

Mitochondrial activation chemicals synergize with surface receptor PD-1 blockade for T cell-dependent antitumor activity

“…Other ROS generators, chaetocin and phytol, however, did not show the synergistic antitumor effect, suggesting they differ quantitatively or qualitatively from Luperox in the ROS generation mechanism in T cells (Fig. S4 A-C) (28,29).…”

CK2 inhibition induced PDK4-AMPK axis regulates metabolic adaptation and survival responses in glioma

“…Immunohistochemistry was performed on tumor tissue samples obtained from either vehicle or TBB treated mice as described previously [26] using antibody against PCNA.…”

miR-429 inhibits glioma invasion through BMK1 suppression

“…Aside from BMK1, three of the four classes of MAP kinases (namely, ERK, JNK, and p38) have been found to promote invasion and migration in glioma [5][6][7]. Previous studies have been reported that BMK1 could suppress the growth of lung cancer [8], whereas other studies have reported that BMK1 could promote metastasis by enhancing EMT in human breast cancer [9].…”