Ferroptosis is a type of regulated cell death that displays a promising therapeutic pathway for drug-resistant tumor cells. However, some pancreatic cancer (PC) cells are less sensitive to erastin-induced ferroptosis, and normal pancreatic cells are susceptible to this newly discovered cell death. Therefore, there is an urgent need to find drugs to enhance the sensitivity of these PC cells to erastin while limiting side effects. Here, we found that the oxidized form of vitamin C-dehydroascorbic acid (DHA) can be transported into PC cells expressing high levels of GLUT1, resulting in ferroptosis. Moreover, pharmacological vitamin C combined with erastin can synergistically induce ferroptosis of PC cells involving glutathione (GSH) reduction and ferrous iron accumulation while inhibiting the cytotoxicity of normal cells. Mechanistically, as a direct system Xc- inhibitor, erastin can directly suppress the synthesis of GSH, and the recycling of vitamin C and DHA is performed through GSH consumption, which is denoted as the classical mode. Furthermore, oxidative stress induced by erastin and vitamin C could enhance the expression of HMOX1 via the AMP-activated protein kinase (AMPK)/nuclear factor erythroid 2-related factor 2 (NRF2) pathway to increase the labile iron level, which is named the nonclassical mode. In vivo experiments showed that erastin and vitamin C can significantly slow tumor growth in PC xenografts. In summary, the combination of erastin and vitamin C exerts a synergistic effect of classical and nonclassical modes to induce ferroptosis in PC cells, which may provide a promising therapeutic strategy for PC.
The KRAS/Lin28B axis maintains stemness of pancreatic cancer cells via the let‐7i/TET3 pathway.
Purpose. Gastric cancer (GC) is a lethal cancer with a poor 5-year relative survival, which requires a new research perspective. Our study aims to explore the biological impact of the mast cell-expressed membrane protein 1 (MCEMP1) in GC, which includes its expression and potential biological functions. Methods. The expression of MCEMP1 was assessed through public databases. The GO, KEGG, and GESA analyses were conducted to explore the biofunction of MCEMP1. And ssGSEA was used to analyze the infiltration of the immune cells for MCEMP1. The proliferation, migration, and invasion of GC cells were analyzed through CCK8, colony-forming, wound healing, Transwell, and Western blot assay. Results. The expression of MCEMP1 was higher in GC tissues. Further, we found a close relationship between MCEMP1 and poorer prognosis of gastric cancer by prognostic analysis. The functional analysis showed that MCEMP1 is involved in immune, inflammation, and metabolism-related pathways. The ssGSEA analysis indicated MCEMP1 mRNA expression was associated with immune infiltration of multiple immune cells. In cellular experiments, the invasion and metastasis of gastric cancer cells could be promoted by regulating the rise of MCEMP1 expression. Western blot analysis showed that regulation of MCEMP1 expression can affect EMT-related protein expression and that NF-κB expression is involved in this process. Conclusion. MCEMP1 shows a potential value for the prognosis in GC. And, abnormal expression of MCEMP1 in GC is correlated with tumor immune cell infiltration. In in vitro experiments, MCEMP1 can affect the proliferation, migration, and invasion of GC cells by regulating EMT, in which TLR4/NOD2/NF-κB was involved.
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