LCT-3d Induces Oxidative Stress-Mediated Apoptosis by Upregulating Death Receptor 5 in Gastric Cancer Cells

Abstract

Gastric cancer is a global health problem. In this study, we investigate the role of a novel Indole derivative, named LCT-3d, in inhibiting the growth of gastric cancer cells by MTT assay. The Western blotting results showed that LCT-3d modulated the mitochondrial-related proteins and Cleaved-Caspases 3/9, to induce cell apoptosis. The up-regulation of Death receptor 5 (DR5) in MGC803 cells was observed with LCT-3d treatment. Knockdown of DR5 on MGC803 cells partially reversed the LCT-3d-induced mitochondrial apoptosis. The level of Reactive Oxygen Species (ROS) in MGC803 cells was increased with LCT-3d treatment and could be blocked with the pretreatment of the ROS inhibitor N-Acetylcysteine (NAC). The results demonstrate that the elevating ROS can up-regulate the expression of DR5, resulting in apoptosis via mitochondrial pathway. Although the nuclear factor erythroid-2 related factor 2 (Nrf2) pathway served an important role in protecting gastric cancer cells against the injury of ROS, it can’t reverse LCT-3d-induced cell apoptosis. Taken together, our study showed that LCT-3d induced apoptosis via DR5-mediated mitochondrial apoptotic pathway in gastric cancer cells. LCT-3d could be a novel lead compound for development of anti-cancer activity in gastric cancer.

Cell death affecting the progression of gastric cancer

“…Another study showed that silencing SIRT6 induced ferroptosis in gastric cancer cells by inducing inactivation of Keap1-Nrf2 and low expression of GPX4, thereby improving the sensitivity of gastric cancer cells to sorafenib [ 87 ]. It has also been shown that ROS accumulation activates the Keap1-Nrf2 signaling pathway in gastric cancer cells, thereby inhibiting apoptosis in gastric cancer cells [ 88 ]. However, LCT-3d induces oxidative stress and apoptosis in gastric cancer cells by upregulating death receptor 5, a process unaffected by Nrf2 activation [ 88 ].…”

“…It has also been shown that ROS accumulation activates the Keap1-Nrf2 signaling pathway in gastric cancer cells, thereby inhibiting apoptosis in gastric cancer cells [ 88 ]. However, LCT-3d induces oxidative stress and apoptosis in gastric cancer cells by upregulating death receptor 5, a process unaffected by Nrf2 activation [ 88 ]. This suggests that the inhibitory effect of the Nrf2 pathway on apoptosis is weak and not readily apparent when other proapoptotic signals are activated.…”