Propofol induces the ferroptosis of colorectal cancer cells by downregulating STAT3 expression

Abstract

Propofol is a commonly used intravenous anesthetic agent that can also suppress the proliferation of various human cancer types, including colorectal cancer (CRC). The present study aimed to investigate whether propofol could induce the ferroptosis of CRC cells by regulating signal transducer and activator of transcription 3 (STAT3). STAT3 expression in normal and CRC tissues was measured. Human normal colonic epithelial NCM460 cells and human CRC SW480 cells were exposed to different concentrations of propofol and then cell 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 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.

SHP-1/STAT3-Signaling-Axis-Regulated Coupling between BECN1 and SLC7A11 Contributes to Sorafenib-Induced Ferroptosis in Hepatocellular Carcinoma

“…Previous studies have shown that sorafenib activates SHP-1 phosphatase and dephosphorylates STAT3 [ 15 ]. Lines of evidence also indicate that STAT3 may serve as a negative regulator of ferroptosis, as suppression of STAT3 activity induces ferroptosis in gastric cancer [ 17 ], while ectopic expression of STAT3 rescues colorectal cancer cells from propofol-triggered ferroptosis [ 14 ]. Hence, we investigated whether the SHP-1/STAT3 signaling pathway is involved in sorafenib-induced ferroptosis in HCC.…”

“…Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that regulates the expression of molecules involved in inflammation, survival, proliferation, and differentiation [ 13 ]. It has been suggested that propofol triggers ferroptosis by reducing the expression of STAT3 in colorectal cancer cells, and that ectopic expression of STAT3 alleviates ferroptosis [ 14 ]. Hence, STAT3 may play a role in the negative regulation of ferroptosis.…”

Network Pharmacology Identifies Therapeutic Targets and the Mechanisms of Glutathione Action in Ferroptosis Occurring in Oral Cancer

“…PTGS2 is responsible for the prostanoid biosynthesis involved in inflammation and mitogenesis ( Gómez-Valenzuela et al, 2021 ). It was reported that upregulation of PTGS2 induces the ferroptosis of colorectal cancer cells ( Zhao and Chen 2021 ); thus, PTGS2 is considered as a marker of ferroptosis. The PTGS2 expression was associated with increased lipid peroxidation in gastric cancer cells ( Guan et al, 2020 ).…”

Cellular landscaping of cisplatin resistance in cervical cancer

“…Furthermore, the administration of certain drugs, such as arctigenin, mahanin, and propofol enhances the induction of cell death by blocking STAT3 [168]. The JAK/STAT pathway is involved in immune activation and regulatory activities, such as tumor cell identification and tumor-driven immune escape [169][170][171][172]. The clinically licensed JAK2 inhibitor ruxolitinib works in tandem with cisplatin to induce cell death in HPV+ CC cells.…”

“…The clinically licensed JAK2 inhibitor ruxolitinib works in tandem with cisplatin to induce cell death in HPV+ CC cells. Ruxolitinib and cisplatin alone decrease proliferation and causes apoptosis, indicating that both therapies might synergistically induce apoptosis in HPV+ CC cells [169][170][171][172].…”