TIGAR Drives Colorectal Cancer Ferroptosis Resistance Through ROS/AMPK/SCD1 Pathway

Colorectal cancer(CRC)is one of the most common malignant tumor of the digestive tract,ranking among the top three in both morbidity and mortality.Ferroptosis is a recently identified type of regulated cell death.Increasing evidence has shown that ferroptosis plays an important regulatory role in the occurrence and development of cancer.TP53-induced glycolysis and apoptosis regulator(TIGAR)has been shown to be highly expressed in colon cancer,the main function of TIGAR is correlated with antioxidant effects.The purpose of this study is to investigate the regulatory role of TIGAR in CRC ferroptosis.Bioinformatics analysis showed that TIGAR expression in CRC tissues is significantly higher than that in adjacent normal tissues.Knockdown of TIGAR significantly caused an increase in erastin-induced ferroptosis in SW620 and HCT116 cells.Notably,knockdown of TIGAR significantly decreased GSH/GSSG ratio,increased lipid peroxidation production,and facilitated the accumulation of lipid peroxidation product malondialdehyde(MDA),and rendered CRC cells more sensitive to erastin induced ferroptosis.The ferroptosis and SCD1 protein expression of CRC are investigated after the treatment of ROS scavenger NAC and AMPK inhibitor Compound C.The results indicate that TIGAR inhibition repressed SCD1 expression in AMPK-dependent manner by increasing intracellular ROS levels.Thus,these results suggest that TIGAR induces ferroptosis resistance in CRC cells via the ROS/AMPK/SCD1 signaling pathway.These findings reveal that TIGAR is a protein assisting CRC cells resisting ferroptosis and it could be a potential target for CRC treatment.