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Abstract
Background
Ferroptosis is involved in the drug resistance mechanisms of some tumors. The present study aimed to explore the role of tissue inhibitor of matrix metalloprotease 1 (TIMP1) in sorafenib-triggered ferroptosis in colorectal cancer (CRC).
Methods
HCT-8 CRC cell lines were generated that were sorafenib-resistant or that under- or overexpressed TIMP1. The levels of reactive oxygen species (ROS), iron, and malondialdehyde (MDA) were compared across the different cell lines. The half-maximal inhibitory concentration of sorafenib against the different lines was determined based on cell viability. Expression of ferroptosis-related genes and the corresponding proteins was determined by quantitative RT-PCR or western blotting.
Results
TIMP1 overexpression induced sorafenib resistance in HCT-8 cells. TIMP1 knockdown repressed the activation of the PI3K/Akt pathway and reduced levels of glutathione peroxidase 4 (GPX4), enhancing sorafenib-induced ferroptosis. This led to accumulation of ROS, iron, and MDA. Giving sorafenib and the GPX4 inhibitor RSL3 to sorafenib-resistant HCT-8 cells induced ferroptosis, leading to elevated levels of iron and lipid peroxides, ultimately reducing cell viability. TIMP1 depletion in CRC cells enhances sorafenib-triggered ferroptosis by reducing PI3K/Akt axis signal transduction.
Conclusion
The combination of sorafenib and GPX4 inhibitors such as RSL3 may be a promising therapy against CRC.
Author contributions
LW and JW conceived and designed the experiments, LC analyzed and interpreted the results of the experiments, LC and LW performed the experiments.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Data availability statement
All data generated or analyzed during this study are included in this published article.