Sinensetin Induces Autophagic Cell Death through p53-Related AMPK/mTOR Signaling in Hepatocellular Carcinoma HepG2 Cells

Abstract

Sinensetin (SIN) has been reported to exhibit anti-inflammatory and anti-cancer activity. However, the cellular and molecular mechanism by which SIN promotes hepatocellular carcinoma (HCC) cell death remains unclear. In the present study, we investigated the induction of cell death by SIN and its underlying mechanism in HepG2 cells, an HCC cell line. We found that SIN significantly induced cell death in HepG2 cells, whereas the proliferation rate of Thle2, human liver epithelial cells, was unaffected by SIN. SIN-treated HepG2 cells were not affected by apoptotic cell death; instead, autophagic cell death was induced through the p53-mediated AMPK/mTOR signaling pathway. Inhibition of p53 degradation led to both autophagy and apoptosis in HepG2 cells. p53 translocation led to SIN-induced autophagy, whereas p53 translocation inhibited SIN-induced apoptosis. However, SIN showed apoptosis in the p53-mutant Hep3B cell line. Molecular docking simulation of the p53 core domain showed effective binding with SIN, which was found significant compared with the known p53 activator, RITA. Collectively, these data suggest that SIN may be a potential anti-cancer agent targeting autophagic cell death in human liver cancer.

Sinensetin Reduces Osteoarthritis Pathology in the Tert-Butyl Hydroperoxide-Treated Chondrocytes and the Destabilization of the Medial Meniscus Model Mice via the AMPK/mTOR Signaling Pathway

“…Autophagy has been proved to be a potential therapeutic target for OA, because it helps to alleviate the apoptosis and senescence of chondrocytes (Appleton, 2018). Previous studies have shown that Sin is an autophagy inducer used to treat colitis and hepatocellular carcinoma (Xiongjian et al, 2019;Kim et al, 2020). In our study, Sin also significantly improved the autophagy function of chondrocytes, and its protective effect on TBHP-treated chondrocytes was abrogated when autophagy was inhibited, indicating that Sin plays a protective role by enhancing autophagy.…”

“…Sin is also involved in the regulation of a variety of signaling pathways, such as NF-kappaB, AKT/mTOR and MAPKs signaling (Tan et al, 2019;Li et al, 2020). A recent study showed that Sin promotes autophagy through AMPK/mTOR signaling pathway to induce hepatocellular carcinoma cell apoptosis (Kim et al, 2020). Although studies have conducted extensive studies on the function of Sin, its effect on chondrocyte autophagy and its potential therapeutic effect on the progression of OA remain unclear.…”

Novel Butein Derivatives Repress DDX3 Expression by Inhibiting PI3K/AKT Signaling Pathway in MCF-7 and MDA-MB-231 Cell Lines

“…This assay has shown a remarkable decline in the cell viability when compared with the untreated cells. The 3a has shown an IC 50 Fundamentally, the flavonoids promote the anticancer mechanism by instigating the apoptosis and cell cycle arrest (42). The apoptosis was studies by the expression of cleaved PARP and cleaved caspase 3 (42).…”

“…The 3a has shown an IC 50 Fundamentally, the flavonoids promote the anticancer mechanism by instigating the apoptosis and cell cycle arrest (42). The apoptosis was studies by the expression of cleaved PARP and cleaved caspase 3 (42). Caspases broadly belong to the protease family that manifests specificity to aspartic acids.…”

Transcriptome analysis of sinensetin-treated liver cancer cells guided by biological network analysis

“…In our previous study on SIN treatment in HepG2 cells, we found that SIN could induce HCC cell death in vitro (22). RNA-seq and Cuffdiff identified 43 DEGs (Table II) between SIN-untreated and SIN-treated HepG2 cells based on the selection criteria (a false discovery rate <0.05 and |log 2 FC| >1).…”