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. 2024 Aug;38(8):3954-3972.
doi: 10.1002/ptr.8258. Epub 2024 Jun 4.

Curcumin suppresses colorectal cancer by induction of ferroptosis via regulation of p53 and solute carrier family 7 member 11/glutathione/glutathione peroxidase 4 signaling axis

Tianqi Ming  1 , Jiarong Lei  1 , Yuhui Peng  1 , Minmin Wang  1 , Yuanjing Liang  1 , Shun Tang  1 , Qiu Tao  1 , Muqing Wang  1 , Xiaomeng Tang  1 , Ziyu He  1 , Xiaohong Liu  1 , Haibo Xu  1
Affiliations

Curcumin suppresses colorectal cancer by induction of ferroptosis via regulation of p53 and solute carrier family 7 member 11/glutathione/glutathione peroxidase 4 signaling axis

Tianqi Ming et al. Phytother Res. 2024 Aug.

Abstract

Driven by iron-dependent lipid peroxidation, ferroptosis is regulated by p53 and solute carrier family 7 member 11 (SLC7A11)/glutathione/glutathione peroxidase 4 (GPX4) axis in colorectal cancer (CRC). This study aimed to investigate the influence of curcumin (CUR) on ferroptosis in CRC. The efficacies of CUR on the malignant phenotype of CRC cells were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide, wound healing, and clonogenic assays. The effects of CUR on ferroptosis of CRC cells were evaluated by transmission electron microscopy, lactate dehydrogenase release assay, Fe2+ staining, and analyses of reactive oxygen species, lipid peroxide, malondialdehyde, and glutathione levels. CUR's targets in ferroptosis were predicted by network pharmacological study and molecular docking. With SW620 xenograft tumors, the efficacy of CUR on CRC was investigated, and the effects of CUR on ferroptosis were assessed by detection of Fe2+, malondialdehyde, and glutathione levels. The effects of CUR on expressions of p53, SLC7A11, and GPX4 in CRC cells and tumors were analyzed by quantitative reverse transcription-polymerase chain reaction, western blotting, and immunohistochemistry. CUR suppressed the proliferation, migration, and clonogenesis of CRC cells and xenograft tumor growth by causing ferroptosis, with enhanced lactate dehydrogenase release and Fe2+, reactive oxygen species, lipid peroxide, and malondialdehyde levels, but attenuated glutathione level in CRC. In silico study indicated that CUR may bind p53, SLC7A11, and GPX4, consolidated by that CUR heightened p53 but attenuated SLC7A11 and GPX4 mRNA and protein levels in CRC. CUR may exert an inhibitory effect on CRC by inducing ferroptosis via regulation of p53 and SLC7A11/glutathione/GPX4 axis.

Keywords: GPX4; SLC7A11; colorectal cancer; curcumin; ferroptosis; p53.

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