Quercetin‐3‐methyl ether inhibits esophageal carcinogenesis by targeting the AKT/mTOR/p70S6K and MAPK pathways

Abstract

Esophageal squamous cell carcinoma (ESCC) is highly prevalent in Asia, especially in China. Research findings indicate that nitrosamines, malnutrition, unhealthy living habits, and genetics contribute to esophageal carcinogenesis. Currently, the 5-year survival rate for ESCC patients remains low, owing in part to a lack of a clear understanding of mechanisms involved. Chemoprevention using natural or synthesized compounds might be a promising strategy to reduce esophageal cancer incidence. The epidermal growth factor receptor (EGFR) can activate downstream pathways including the phosphatidylinositol 3-kinase (PI3K) pathway and the Ras/mitogen-activated protein kinase (MAPK) pathways. Among the important players, AKT and ERKs have an important relationship with cancer initiation and progression. Here, we found that phosphorylated (p)-AKT and p-ERKs were highly expressed in esophageal cancer cell lines and in esophageal cancer patients. Human phospho-kinase array and pull-down assay results showed that quercetin-3-methyl ether (Q3ME) is a natural flavonoid compound that interacted with AKT and ERKs and inhibited their kinase activities. At the cellular level, Q3ME attenuated esophageal cancer cell proliferation and anchorage-independent growth. Western blot analysis showed that this compound suppressed the activation of AKT and ERKs downstream signaling pathways, subsequently inhibiting activating protein-1 (AP-1) activity. Importantly, Q3ME inhibited the formation of esophageal preneoplastic lesions induced by N-nitrosomethylbenzylamine (NMBA). The inhibition by Q3ME was associated with decreased inflammation and esophageal cancer cell proliferation in vivo. Collectively, our data suggest that Q3ME is a promising chemopreventive agent against esophageal carcinogenesis by targeting AKT and ERKs.

Mefloquine Inhibits Esophageal Squamous Cell Carcinoma Tumor Growth by Inducing Mitochondrial Autophagy

“…ESCC cell lines KYSE150 and KYSE450 cells were purchased from the Chinese Academy of Sciences cell bank (Shanghai, China). Before freezing and culture, cells were cytogenetically tested by STR-Promega and authenticated (August, 2014 and July, 2017) as described previously ( 14 ). Cells were cultured at 37°C in a 5% CO 2 incubator.…”

The Establishment of Esophageal Precancerous Lesion Model by Using p53 Conditional Knockout Mouse in Esophageal Epithelium

“…Dysplasia is composed of increased cellular atypia, disorderly epidermal cells and basal layer cell, and more obvious thickening of the keratin layer. According to the degree of cytologic atypia, dysplasia was categorized as mild dysplasia (affect <1/3 of epithelium), moderate dysplasia (affect 1/3 to 2/3 of epithelium), and severe dysplasia (affect >2/3 of epithelium) [22]. e lesions at all levels from the esophagus of each mouse were counted and the total number of each histological category per group was recorded.…”

Quercetin radiosensitizes non‐small cell lung cancer cells through the regulation of miR‐16‐5p/WEE1 axis

“…Quercetin is a biologically active plant flavonoid with anti‐tumor activities . For instance, quercetin‐3‐methyl ether exerts an inhibitory effect on the development of esophageal cancer via targeting the AKT/mTOR/p70S6K and MAPK signaling pathways; quercetin impedes the proliferation of hepatoma cells and induces their apoptosis via repressing the JAK2/STAT3 signaling pathway; in osteosarcoma, quercetin inhibits the proliferation and metastasis of tumor cells via suppressing the expression of parathyroid hormone receptor 1 . Moreover, quercetin enhances the radiosensitivity of tumor cells via modulating the expression of ATM kinase .…”