Echinatin suppresses esophageal cancer tumor growth and invasion through inducing AKT/mTOR-dependent autophagy and apoptosis

Abstract

Esophageal squamous cell carcinoma (ESCC) is one of the most common malignant tumors with poor survival. It is urgent to search for new efficient drugs with good stability and safety for clinical therapy. This study aims to identify potential anticancer drugs from a compound library consisting of 429 natural products. Echinatin, a compound isolated from the Chinese herb Glycyrrhiza uralensis Fisch, was found to markedly induce apoptosis and inhibit proliferation and colony-formation ability in ESCC. Confocal fluorescence microscopy data showed that echinatin significantly induced autophagy in ESCC cells, and autophagy inhibitor bafilomycinA1 attenuated the suppressive effects of echinatin on cell viability and apoptosis. Mechanistically, RNA sequencing coupled with bioinformatics analysis and a series of functional assays revealed that echinatin induced apoptosis and autophagy through inactivation of AKT/mTOR signaling pathway, whereas constitutive activation of AKT significantly abrogated these effects. Furthermore, we demonstrated that echinatin had a significant antitumor effect in the tumor xenograft model and markedly suppressed cell migration and invasion abilities of ESCC cells in a dose-dependent manner. Our findings provide the first evidence that echinatin could be a novel therapeutic strategy for treating ESCC.

Maprotiline Suppresses Cholesterol Biosynthesis and Hepatocellular Carcinoma Progression Through Direct Targeting of CRABP1

“…Cholesterol metabolism has been proven to promote the survival and drug resistance of tumor cells to a certain extent ( Silvente-Poirot and Poirot, 2014 ; Yan et al, 2020 ). We have confirmed that the AKT/ERK pathway participates in the growth and metastasis of cancer cells in our previous studies, and this pathway has been proven to be the target of many anticancer drugs ( Xu et al, 2018 ; Hong et al, 2020 ; Xu et al, 2020 ; Hu et al, 2021 ). An increasing number of studies have confirmed that SREBP2 indeed plays a cancer-promoting role by regulating cholesterol metabolism in HCC ( Yang et al, 2019 ; Che et al, 2020 ; Liu et al, 2020 ), and SREBP2 has been proven to be the target of some anticancer drugs ( Kim et al, 2018 ; Kim et al, 2019 ).…”

Echinatin mitigates H2O2-induced oxidative damage and apoptosis in lens epithelial cells via the Nrf2/HO-1 pathway

“…Importantly, it has been reported that Ech can inhibit activation of the NF-κB pathway 56 and the AKT/mTOR pathway. 57 Therefore, the protective effect of Ech may also involve other signal pathways, a hypothesis that needs further study. In addition, because the potential toxicity and side effects of Ech and its derivatives are still unclear, there is still a lot of research to be performed before this drug can be applied in the clinic.…”

Lomerizine 2HCl inhibits cell proliferation and induces protective autophagy in colorectal cancer via the PI3K/Akt/mTOR signaling pathway

“…The experiments were executed as previously described 41 . CRC cells were exposed to varied concentrations of lomerizine 2HCl and fixed with methanol.…”

“…The experiments were executed as previously described. 41 CRC cells were exposed to varied concentrations of lomerizine 2HCl and fixed with methanol. Then, after treating with 0.5% Triton X‐100, cells were blocked with 5% goat serum and treated with primary antibodies overnight at 4°C.…”