Thiostrepton induces ferroptosis in pancreatic cancer cells through STAT3/GPX4 signalling

Abstract

Ferroptosis is a new form of regulated cell death that is mediated by intracellular iron and ester oxygenase, and glutathione-dependent lipid hydroperoxidase glutathione peroxidase 4 (GPX4) prevents ferroptosis by converting lipid hydroperoxides into nontoxic lipid alcohols. Although thiostrepton (TST) has been reported to exert antitumor effects, its role in pancreatic cancer and the underlying mechanisms remain unclear. In this study, we found that TST reduced the viability and clonogenesis of pancreatic cancer cell lines, along with intracellular iron overload, increasing reactive oxygen species (ROS) accumulation, malondialdehyde (MDA) overexpression, and glutathione peroxidase (GSH-PX) depletion. Mechanistically, chromatin immunoprecipitation (ChIP) and dual luciferase reporter gene assays were used to confirm that signal transducer and activator of transcription 3 (STAT3) binds to the GPX4 promoter region and promotes its transcription, whereas TST blocked GPX4 expression by regulating STAT3. Finally, in vivo experiments revealed that TST inhibited the growth of subcutaneously transplanted tumours and had considerable biosafety. In conclusion, our study identified the mechanism by which TST-induced ferroptosis in pancreatic cancer cells through STAT3/GPX4 signalling.

High‑throughput screening identification of a small‑molecule compound that induces ferroptosis and attenuates the invasion and migration of hepatocellular carcinoma cells by targeting the STAT3/GPX4 axis

“…Furthermore, the phyto-sesquiterpene lactones, DET and DETD-35, have been found to induce ferroptosis in mutant melanoma through the inhibition of GPX4 ( 24 ). The findings of the present study are consistent with those of other research ( 25 ), demonstrating that GPX4 expression in HCC cells is negatively associated with the PPVI concentration. These findings provide new evidence of the anticancer effects of PPVI on HCC, particularly by the induction of ferroptosis.…”

Curcumin Analog, HO‐3867, Induces Both Apoptosis and Ferroptosis via Multiple Mechanisms in NSCLC Cells with Wild‐Type p53

“…HO-3867 is a STAT3 inhibitor [ 19 ]. Many studies suggest that STAT3 participates in the upregulation of GPX4 in various cells [ 45 , 46 ]. Therefore, we hypothesized that HO-3867 downregulated GPX4 via inhibition of STAT3 and did not experimentally confirm it.…”

Combination treatment with FAAH inhibitors/URB597 and ferroptosis inducers significantly decreases the growth and metastasis of renal cell carcinoma cells via the PI3K-AKT signaling pathway

“…Increasing studies have classified that pivotal role of ferroptosis in the occurrence and development of neurodegenerative diseases, infections, and inflammatory diseases and carcinogenesis [17][18][19]. In recent years, the inducing of ferroptosis in tumor cells has become a potential strategy for tumor therapy by modulating various tumor properties, and various ferroptosis inducing agents or drugs such as sulfasalazine, erastin, RSL3, sorafeinib have been developed in reducing cancer growth and resistance [20][21][22]. Nevertheless, the unsatisfactory antitumor pharmacological effect in vivo of ferroptosis inducers single agent and low selectivity for normal cell types limit the application of ferroptosis in clinical cancer therapy, which motivating novel strategies [11].…”

“…This indicates that combination therapy targeting lipid metabolism and ferroptosis is a promising cancer therapy [23][24][25]. In this process, Glutathione Peroxidase 4 (GPX4) is the most important regulator of iron death-related mechanisms, and RSL3, as a small-molecule inhibitor of GPX4, is currently the most commonly used Ferroptosis inducer [20][21][22][23][24][25]. Moreover, the endocannabinoid system exerts anticarcinogenic effects via multiple mechanisms, including proapoptotic and antiproliferative properties [26][27][28].…”