AMER1 deficiency promotes the distant metastasis of colorectal cancer by inhibiting SLC7A11- and FTL-mediated ferroptosis

Siqin Lei; Chaoyi Chen; Fengyan Han; Jingwen Deng; Dongdong Huang; Lili Qian; Ming Zhu; Xiaohui Ma; Maode Lai; Enping Xu; Honghe Zhang

doi:10.1016/j.celrep.2023.113110

AMER1 deficiency promotes the distant metastasis of colorectal cancer by inhibiting SLC7A11- and FTL-mediated ferroptosis

Cell Rep. 2023 Sep 26;42(9):113110. doi: 10.1016/j.celrep.2023.113110. Epub 2023 Sep 8.

Authors

Siqin Lei¹, Chaoyi Chen², Fengyan Han¹, Jingwen Deng¹, Dongdong Huang³, Lili Qian⁴, Ming Zhu¹, Xiaohui Ma⁵, Maode Lai⁶, Enping Xu⁷, Honghe Zhang⁸

Affiliations

¹ Department of Pathology and International Institutes of Medicine, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Research Unit of Intelligence Classification of Tumor Pathology and Precision Therapy, Chinese Academy of Medical Sciences (2019RU042), Hangzhou 310058, China.
² Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, Zhejiang Provincial Clinical Research Center for Cancer, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China; Cancer Center, Zhejiang University, Hangzhou, Zhejiang 310058, China.
³ The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China.
⁴ Cancer Center, Department of Pathology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310014, China.
⁵ Pharmacology & Toxicology Research Center, The State Key Laboratory of Core Technology in Innovative Chinese Medicine, Tasly Academy, Tasly Holding Group Co., Ltd., Tianjin 300410, China.
⁶ Department of Pathology, Zhejiang University School of Medicine, Research Unit of Intelligence Classification of Tumor Pathology and Precision Therapy of the Chinese Academy of Medical Sciences (2019RU042), Hangzhou 310058, China; Key Laboratory of Disease Proteomics of Zhejiang Province, Zhejiang University, Hangzhou 310058, China.
⁷ Department of Pathology, Zhejiang University School of Medicine, Research Unit of Intelligence Classification of Tumor Pathology and Precision Therapy of the Chinese Academy of Medical Sciences (2019RU042), Hangzhou 310058, China; Key Laboratory of Disease Proteomics of Zhejiang Province, Zhejiang University, Hangzhou 310058, China. Electronic address: xep@zju.edu.cn.
⁸ Department of Pathology and International Institutes of Medicine, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Research Unit of Intelligence Classification of Tumor Pathology and Precision Therapy, Chinese Academy of Medical Sciences (2019RU042), Hangzhou 310058, China; Key Laboratory of Disease Proteomics of Zhejiang Province, Zhejiang University, Hangzhou 310058, China. Electronic address: honghezhang@zju.edu.cn.

PMID: 37682704
DOI: 10.1016/j.celrep.2023.113110

Abstract

The crosstalk between ferroptosis and cancer metastasis remains unclear. Here, we identify AMER1 as a key regulator of ferroptosis. AMER1 loss causes resistance to ferroptosis in colorectal cancer (CRC) cells. Interestingly, AMER1-deficient CRC cells preferentially form distant metastases, while AMER1-naive CRC cells mainly invade lymph nodes. Moreover, the ferroptosis inhibitor liproxstatin-1 effectively promotes hematogenous transfer of AMER1-naive cells. Mechanistically, AMER1 binds to SLC7A11 and ferritin light chain (FTL) and recruits β-TrCP1/2, which degrade SLC7A11 and FTL by ubiquitination. Therefore, AMER1 deficiency increases cellular cystine levels but decreases the pool of labile free iron, thereby enhancing resistance to ferroptosis in CRC cells. Thus, AMER1 deficiency increases the survival of CRC cells in the blood under conditions of high oxidative stress and then promotes hematogenous metastasis of CRC. In conclusion, AMER1 mediates the crosstalk between ferroptosis and cancer metastasis, which provides a window of opportunity for treating metastatic colorectal cancer patients with AMER1 mutations.

Keywords: AMER1; CP: Cancer; FTL; SLC7A11; colorectal cancer; ferroptosis; metastasis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing
Amino Acid Transport System y+ / genetics
Apoferritins
Colonic Neoplasms*
Colorectal Neoplasms* / genetics
Cross Reactions
Cystine
Ferroptosis*
Humans
Tumor Suppressor Proteins

Substances

Apoferritins
Cystine
SLC7A11 protein, human
Amino Acid Transport System y+
FTL protein, human
AMER1 protein, human
Tumor Suppressor Proteins
Adaptor Proteins, Signal Transducing