2. Academic Validation
  3. High-fat diet aggravates colitis-associated carcinogenesis by evading ferroptosis in the ER stress-mediated pathway

High-fat diet aggravates colitis-associated carcinogenesis by evading ferroptosis in the ER stress-mediated pathway

  • Free Radic Biol Med. 2021 Dec;177:156-166. doi: 10.1016/j.freeradbiomed.2021.10.022.
Xiaoli Zhang 1,  Weiwei Li 2,  Yiming Ma 2,  Xinhua Zhao 2,  Longmei He 2,  Peng Sun 3,  Hongying Wang 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Gastrointestinal Surgery, Peking University Shenzhen Hospital, Shenzhen, China.
  • 2 State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
  • 3 Department of Gastrointestinal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China.
  • 4 State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Electronic address: hongyingwang@cicams.ac.cn.
PMID: 34688836 DOI: 10.1016/j.freeradbiomed.2021.10.022
Abstract

Ferroptosis, a type of programmed cell death caused by lipid peroxidation has recently been observed in colitis. Whether a high-fat diet (HFD) affects Ferroptosis and whether it contributes to colitis-associated carcinogenesis (CAC) has not been explored. We found iron, lipid peroxidation, and ferroptotic markers to be elevated in AOM/DSS (azoxymethane/dextran sulfate sodium)-induced mouse CAC model. Transmission electron microscopy also confirmed the occurrence of Ferroptosis in colonic tissues. Treatment with the Ferroptosis inhibitor, ferrostatin-1 increased the incidence of CAC. Compared with iso-caloric control mice, HFD mice exhibited increased tumor number and a higher degree of dysplasia following repression of lipid peroxidation and Ferroptosis marker expression in mouse colon tissue. Furthermore, Ferroptosis markers were negatively correlated with the tumor number in mice. In vitro, a lipid mixture blocked Ferroptosis in various colorectal Cancer cell lines and inhibited GSH degradation by negatively regulating CHAC1, a target in ER stress signaling. Finally, the Ferroptosis inducer partly abolished the pro-tumor effect of the HFD on CAC in vivo. Collectively, these findings suggest that a HFD aggravates CAC through the evasion of Ferroptosis in the ER stress-mediated pathway and provide a new perspective for CAC prevention in the future.

Keywords

CHAC1; Colitis-associated carcinogenesis; Endoplasmic reticulum stress; Ferroptosis; High-fat diet.

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