Quercetin Regulates Sestrin 2-AMPK-mTOR Signaling Pathway and Induces Apoptosis via Increased Intracellular ROS in HCT116 Colon Cancer Cells

Abstract

Background:The suppression of abnormal cell proliferation is therapeutic strategies for the treatment of cancer. In this study, we investigated the regulatory mechanism of quercetin-induced apoptosis through regulation of Sestrin 2 and AMPK signaling pathway.Methods:After treatment of quercetin to colon cancer cells, intracellular ROS was detected using by DCFH-DA. To examine how quercetin and H2O2 induced apoptosis, we analyzed the change of Sestrin 2, p53 expression and p-AMPKα1, p-mTOR levels by Western blotting. To evaluate the effect of intracellular ROS generated by quercetin on colon cancer cells, NAC, anti-oxidative agent, was co-treated.Results:Quercetin increased apoptotic cell death though generating intracellular reactive oxygen species (ROS), and it was responsible for Sestrin 2 expression. Increased Sestrin 2 expression was accompanied by AMPK activation. Interestingly, mTOR activity by Sestirn 2 expression was dependent on AMPK phosphorylation. On the other hand, the expression of Sestrin 2 by quercetin-generated intracellular ROS was independent of p53.Conclusions:We suggested that quercetin-induced apoptosis involved Sestrin 2/AMPK/mTOR pathway, which was regulated by increased intracellular ROS by quercetin.

Pro-oxidant activity of polyphenols and its implication on cancer chemoprevention and chemotherapy

“…of the mitochondrial membrane potential, thereby triggering the intrinsic mitochondrial apoptotic pathway [90]. Quercetin-induced apoptosis in colon cancer HCT116 cells also involved intracellular formation of ROS and the AMPK/mTOR pathway, and these effects where prevented by NAC [91].…”

Recent Insights into the Biological Functions of Sestrins in Health and Disease

“…Kim et al, found that Sesn2 has an important role in regulating the apoptosis process induced by quercetin in HCT116 colon cancer cells [31]. Further reports from the same group demonstrated that not only the Sesn2/AMPK/mTOR pathway but also the Sesn2/AMPK/p38 mitogen-activated protein kinase (MAPK) signaling pathway were involved in the pro-apoptosis effect of quercetin on colon cancer [31, 32].…”

“…Kim et al, found that Sesn2 has an important role in regulating the apoptosis process induced by quercetin in HCT116 colon cancer cells [31]. Further reports from the same group demonstrated that not only the Sesn2/AMPK/mTOR pathway but also the Sesn2/AMPK/p38 mitogen-activated protein kinase (MAPK) signaling pathway were involved in the pro-apoptosis effect of quercetin on colon cancer [31, 32]. Then, researchers found that the overexpression of Sesn2 could inhibit the migration and invasion of HCT116 cells and suppress the tumor growth in a mouse xenograft model through degradating of HIF-1α via AMPK-prolyl hydroxylase pathways [33].…”

Sestrin 2 Attenuates Rat Hepatic Stellate Cell (HSC) Activation and Liver Fibrosis via an mTOR/AMPK-Dependent Mechanism

“…Sestrin 2 acts as an inhibitor of mTOR by upregulating the activation of AMPK [22]. Interestingly, Sestrin 2-knockout mice fed a high-fat diet displayed mTOR-S6K inactivation [9].…”