Zingiberensis Newsaponin Inhibits the Malignant Progression of Hepatocellular Carcinoma via Suppressing Autophagy Moderated by the AKR1C1-Mediated JAK2/STAT3 Pathway

Abstract

Objective. Saponins are a group of compounds from various plants, which exhibit an anticancer activity. This study aimed to explore the anticancer effect of zingiberensis newsaponin (ZnS) against hepatocellular carcinoma (HCC) and the underlying mechanism involving autophagy. Methods. HCC cells (Huh7 and SMMC7721) were treated with ZnS and/or 3-MA. The cell viability, migration, and apoptosis were determined using CCK-8 assay, transwell assay, and flow cytometry, respectively. The levels of oxidative stress markers (ROS, SOD, and MDA) were measured by ELISA assay. Autophagy was monitored using MDC assay, immunofluorescence staining, and transmission electron microscopy. The relative protein expression of LC3II/LC3I, P62, AKR1C1, p-JAK2, p-STAT3, JAK2, and STAT3 was determined using Western blot. Results. ZnS or 3-MA inhibited the cell viability and migration, and it promoted cell apoptosis and oxidative stress in HCC. MDC-positive cells and autophagosomes were reduced by ZnS or 3-MA treatment. The expression of autophagy-related proteins LC3 (LC3II/LC3I) and P62 was, respectively, downregulated and upregulated after ZnS or 3-MA treatment. In addition, ZnS or 3-MA suppressed the protein expression of AKR1C1, p-JAK2, and p-STAT3 in HCC cells. Furthermore, the above phenomena were evidently enhanced by ZnS combined 3-MA treatment. AKR1C1 overexpression weakened the effect of ZnS on inhibiting the expression of AKR1C1, p-JAK2, and p-STAT3. Conclusion. ZnS exerts an anticancer effect on HCC via inhibiting autophagy moderated by the AKR1C1-mediated JAK2/STAT3 pathway. ZnS and 3-MA exert a synergistic effect on inhibiting HCC.

Choline suppresses hepatocellular carcinoma progression by attenuating AMPK/mTOR-mediated autophagy via choline transporter SLC5A7 activation

“…In line with our findings, Alhamad et al reported that after spautin-inhibited autophagy, HCC cells were sensitized to fingolimod treatment ( 36 ). He et al revealed that zingiberensis newsaponin-impaired autophagy inhibited HCC malignant progression ( 37 ). Overall, the above findings suggest that targeting autophagy with nutrients or natural products may inhibit HCC progression and provide a new strategy for HCC treatment.…”

Magnesium Demethylcantharidate induces apoptosis in hepatocellular carcinoma cells via ER stress

“…HCC is a serious threat to human health due to its high incidence and mortality (He et al, 2021;Piñero et al, 2020). In recent decades, many researchers found that certain natural products can kill HCC cells, and it would also be interesting to explore the anti-tumor molecular mechanisms.…”

Deciphering STAT3 signaling potential in hepatocellular carcinoma: tumorigenesis, treatment resistance, and pharmacological significance

“…Notably, suppression of ROS /STAT3/autophagy enhances the ability of capsaicin to stimulate apoptosis in HCC cells [ 88 ]. Moreover, Zingiberensis newsaponin reduces the expression of AKR1C to suppress the Janus kinase 2 (JAK2)/STAT3 axis, thereby inhibiting autophagy and reducing the malignancy of HCC cells [ 89 ].…”