Quercetin regulates the sestrin 2-AMPK-p38 MAPK signaling pathway and induces apoptosis by increasing the generation of intracellular ROS in a p53-independent manner

Abstract

The induction of apoptosis in cancer cells is a therapeutic strategy for the treatment of cancer. In the present study, we investigated the regulatory mechanisms responsible for quercetin-induced apoptosis, mamely the increased expression of sestrin 2 and the activation of the 5′ AMP-activated protein kinase (AMPK)/p38 MAPK signaling pathway. Our results revealed that quercetin induced apoptosis by generating the production of intracellular reactive oxygen species (ROS) and increasing the expression of sestrin 2. The induction of apoptosis by quercetin occurred through the activation of the AMPK/p38 signaling pathway and was dependent on sestrin 2. However, the silencing of sestrin 2 using small interfering RNA (siRNA) targeting sestrin 2 revealed that quercetin did not regulate AMPK or p38 phosphorylation in the cells in which sestrin 2 was silenced. On the other hand, it has been previously reported that sestrin 2 expression is not dependent on p53 expression under hypoxic conditions, whereas DNA damage is dependent on p53. We demonstrate that the increase in the expression of sestrin 2 by quercetin-generated intracellular ROS is p53-independent. The increased expression of sestrin 2 induced apoptosis through the AMPK/p38 signaling pathway in the HT-29 colon cancer cells, which are p53 mutant, treated with quercetin. Thus, our data suggest that quercetin induces apoptosis by reducing mitochondrial membrane potential, generating intracellular ROS production and increasing sestrin 2 expression through the AMPK/p38 pathway. In addition, p53 is not a necessary element for an apoptotic event induced by sestrin 2.

Torilis japonica extract-generated intracellular ROS induces apoptosis by reducing the mitochondrial membrane potential via regulation of the AMPK-p38 MAPK signaling pathway in HCT116 colon cancer

“…Previous studies found that p38 MAPK activation may be regulated by p53 expression and activation via downstream signaling pathways (41,42). Also, the AMPK/p38 MAPK pathway controls apoptosis-related protein expression and induces apoptotic cell death without p53 activation (28). From our results and those of previous studies, we conclude that TJE induces apoptosis and downregulates the mitochondrial outer membrane potential via the AMPK/ p38 MAPK signaling pathway in a p53-indepent manner.…”

“…For this reason, there has been an increased interest in the effect of compounds extracted from natural sources on the prevention and treatment of colorectal cancer. Such compounds induce apoptosis and arrest metastasis through the regulation of intracellular signaling in cancer cells (27)(28)(29)(30)(31)(32)(33). Many researchers have identified food extracts that have been used in cancer chemotherapy experiments.…”

“…Induction of intracellular ROS in cancer cells by treatment with natural compounds is an appealing option in the development of anticancer agents. Increasing ROS by treatment with natural products not only controls the cell cycle but also induces apoptotic cell death by regulating intracellular signaling molecules such as the Bcl-2 family and caspases (12,13,28,(32)(33)(34)(35). Thus, we hypothesized that TJE treatment effects cancer cells through an increase in intracellular ROS.…”

Quercetin Inhibits Cell Migration and Invasion in Human Osteosarcoma Cells

“…Quercetin exerts its anticancer effects by inducing cell cycle arrest, apoptosis, and differentiation and by suppressing MMP secretion [48]. Moreover, quercetin also reduces tumor cell adhesion, invasiveness, metastasis, and angiogenesis [49, 50]. Therefore, we aspired to evaluate the effects of quercetin on tumor migration and invasion.…”

Preparation, in vitro and in vivo evaluation of polymeric nanoparticles based on hyaluronic acid-poly(butyl cyanoacrylate) and D-alpha-tocopheryl polyethylene glycol 1000 succinate for tumor-targeted delivery of morin hydrate

“…Following supernatant aspiration, the cells were washed with PBS twice and then resuspended in 0.5 mL of PBS prior to fluorescent intensity measurements. 31 32 15 µg/mL nystatin, 33 50 µM amiloride, 34 and 10 mg/mL HA. After preincubation for 1 hour, the nanoparticles were added and incubated for a further 2 hours.…”