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

Cell Reports (Sep 2023)

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

Affiliations

Siqin Lei: 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
Chaoyi Chen: 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
Fengyan Han: 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
Jingwen Deng: 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
Dongdong Huang: The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China
Lili Qian: Cancer Center, Department of Pathology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang 310014, China
Ming Zhu: 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
Xiaohui Ma: 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
Maode Lai: 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
Enping Xu: 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; Corresponding author
Honghe Zhang: 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; Corresponding author

Journal volume & issue: Vol. 42, no. 9
p. 113110

Abstract

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Summary: 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.

CP: Cancer

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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