Quercetin inhibits the growth of human gastric cancer stem cells by inducing mitochondrial-dependent apoptosis through the inhibition of PI3K/Akt signaling

Abstract

Cancer stem cells (CSCs) have recently been linked to new treatment strategies for gastric cancer due to the critical role which they play as the 'heartbeat' of cancer. In the present study, we explored the effects of quercetin, an anti-inflammatory and antiviral compound, on gastric CSCs (GCSCs). We noted that quercetin exerted pronounced inhibitory effects on GCSC survival. Moreover, quercetin induced cell apoptosis in a mitochondrial-dependent manner, as shown by the reduction in mitochondrial membrane potential, the activation of caspase-3 and -9, and the downregulation of Bcl-2, as well as the upregulation of Bax and cytochrome c (Cyt-c). Additionally, a marked decrease in Akt phosphorylation levels was observed following treatment with quercetin, whereas pre-treatment with fumonisin B1 (FB1, Akt activator) significantly attenuated the inhibitory effects of quercetin on cell growth and its promoting effects on mitochondrial-dependent apoptosis. Notably, FB1 enhanced the expression of Bcl-2, which was inhibited by quercetin, and prevented the decrease in mitochondrial membrane potential induced by quercetin. However, the increase in the levels of caspases, Bax and Cyt-c induced by quercetin was also attenuated by the addition of FB1 to the GCSCs. Therefore, our results demonstrate that quercetin triggers mitochondrial apoptotic-dependent growth inhibition via the blockade of phosphoinositide 3-kinase (PI3K)-Akt signaling in GCSCs, indicating a potential target for the treatment of gastric cancer.

The aflatoxin B1‐fumonisin B1 toxicity in BRL‐3A hepatocytes is associated to induction of cytochrome P450 activity and arachidonic acid metabolism

“…Later, a severely damaged DNA probably exceeding the repair capacities in cells treated with the mycotoxin mixture may have led to membrane depolarization and apoptosis, which plays a crucial role in maintaining genomic integrity by selectively removing the most heavily impaired cells from the population . Despite it was previously reported that FB 1 prevented the mitochondrial membrane depolarization in human gastric cancer MGC‐803 cells and in rat primary retinal cultures; in this work, the oxidative stress induced by the mycotoxin combination could be responsible by the mitochondrial membrane depolarization that leads to cell apoptosis. The exposure of BRL‐3A cells to AFB 1 and FB 1 individually did lead neither to mitochondrial membrane depolarization nor to cell death, potentially due to nonlethal DNA damage at least partially reverted within the G1‐phase arrest induced by the mycotoxins individually.…”

“…Later, a severely damaged DNA probably exceeding the repair capacities in cells treated with the mycotoxin mixture may have led to membrane depolarization and apoptosis, which plays a crucial role in maintaining genomic integrity by selectively removing the most heavily impaired cells from the population. 30 Despite it was previously reported that FB 1 prevented the mitochondrial membrane depolarization in human gastric cancer MGC-803 cells 52 37 who have shown that under similar experimental conditions, AFB 1 and FB 1 individually did not alter the BRL-3A cell viability. Moreover, jointly they could be indicating a relatively higher resistance of these hepatic cells to the toxins, as other authors demonstrated that AFB 1 and FB 1 alone can induce cell death in several cell types.…”

Traditional Chinese medicine as a cancer treatment: Modern perspectives of ancient but advanced science

“…Prostate cancer stem cell↓; Breast cancer stem cells↓; Glioblastoma stem cells↓; Gastric cancer stem cells↓; Colorectal cancer stem cells↓; Pancreatic cancer stem↓…”

Expression and function of transforming growth factor-β-activated protein kinase 1 in gastric cancer

“…Previous studies have demonstrated that cleaved caspase 3 has an important role in the apoptosis of gastric cancer cells. High protein expression level of cleaved caspase 3 significantly promoted the apoptosis of gastric cancer cells, whereas downregulation of Bcl-2 promoted cyt c release and induced the apoptosis of gastric cancer cells (32–35). Importantly, cleaved caspase 3 and Bcl-2 were both regulated by NF-κB signaling pathways (36–38).…”