In addition, experiments using ferroptosis inhibitor (ferrostatin-1) were not conducted to distinguish between ferroptosis and apoptosis

In addition, experiments using ferroptosis inhibitor (ferrostatin-1) were not conducted to distinguish between ferroptosis and apoptosis. viability was detected. SW480 cells were transfected with a vector overexpressing STAT3 and treated with propofol, and the cell viability, colony formation, cell proliferation, iron level, ROS production and ferroptosis of these cells and control cells were evaluated. Overall, the results showed that STAT3 was highly expressed in CRC tissues. Propofol exerted no marked effect on NCM460 cell viability, but inhibited SW480 cell viability in a concentration-dependent manner. Meanwhile, STAT3 was downregulated by propofol in a concentration-dependent manner. Propofol also inhibited CRC cell proliferation and colony formation, and enhanced cellular iron and ROS levels. Additionally, the expression of proteins involved LG-100064 in ferroptosis was also altered by propofol, including the upregulation of CHAC1 and PTGS2 expression in CRC cells, and the inhibition of GPX4 expression. However, STAT3 overexpression blocked the effect of propofol on CRC cells. In conclusion, propofol may trigger the ferroptosis of CRC cells by downregulating STAT3 expression. and animal model experiments, a number of small molecular ferroptosis inducers (e.g., erastin, sorafenib and sulfasalazine) have shown beneficial antitumor effects (23), and some anticancer drugs approved by the US Food and Drug Administration have been identified as inducers of ferroptosis (24C26). For example, sorafenib was discovered to increase the levels of lipid oxidation in hepatocellular carcinoma, which led to cell death. Notably, administration of a specific inhibitor of ferroptosis, ferrostatin-1, prevented this effect, while inhibitors of apoptosis and necrosis were unable to prevent this effect (27). In pancreatic cancer, activation of the heat shock protein A5 (HSPA5)/GPX4 signaling pathway induced resistance to gemcitabine, while the knockdown of HSPA5 or GPX4 reversed this drug resistance. Ferroptosis was discovered to play an important role in this process, as GPX4 is known to decrease the accumulation of lipid-free radicals and prevent the occurrence and development of ferroptosis (28,29). A previous study reported that artemisinin and its derivatives triggered ferroptosis in pancreatic cancer cells with gene mutations in KRAS, LG-100064 but exerted minimal toxic effects on normal cells (30). Proanthocyanidin treatment markedly suppressed the levels of iron, TBAR, acyl-CoA synthase 4 and arachidonate 15-lipoxygenase type B, while upregulating the levels of GSH, GPX4, erythroid 2-related factor 2 and heme oxygenase-1 in cases of spinal cord trauma. To the best of our knowledge, the current study was the first to discover that propofol could promote ferroptosis in CRC cells. Ferroptosis, which is characterized by iron accumulation and lipid peroxidation, is believed to be related to tumor cell death (10), and the present results showed that TBAR level and both the cellular total iron and Fe2+ levels were significantly increased by propofol treatment. The accumulation of ROS is a characteristic of ferroptosis, and the current study also found that ROS levels were significantly increased in CRC cells upon propofol stimulation. These findings were consistent with the results of previous studies, indicating that propofol may induce ROS-mediated apoptosis in cancer cells (15,16). Ferroptosis is tightly controlled by GPX4 and certain iron transport regulatory proteins. A previous study reported that GPX4 inactivation promoted lipid peroxide accumulation during ferroptosis in CRC (13). The activating transcription factor 4 (ATF4) branch is the predominant signaling pathway activated by ferroptotic reagents; CHAC1 is downstream of ATF4 and has been demonstrated to LG-100064 promote the degradation of GSH and subsequently induce ferroptosis (31,32). PTGS2 is also induced in cells undergoing ferroptosis (33); however, the exact role of PTGS2 in the ferroptotic cell death cascade remains to be elucidated. Previous studies reported that, inhibiting PTGS2, which LG-100064 is induced by ferroptosis, was an effective method for alleviating cell death (33,34). The present Rabbit Polyclonal to Tau study analyzed the expression levels of GPX4, CHAC1 and PTGS2 in CRC cells following propofol treatment. Consistent with the aforementioned experimental results, propofol treatment markedly downregulated GPX4 expression levels, but upregulated CHAC1 and PTGS2 expression levels. These data suggested that, consistent with other ferroptosis inducers, propofol may be able to enhance cellular iron levels and ROS accumulation, as well as upregulate the expression levels of CHAC1 and PTGS2, while downregulating those of GPX4. There are certain limitations to the present study. For example, cell death assays for detecting PI uptake or LDH release were not performed to.

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