Hypoxia-induced cysteine metabolism reprogramming is crucial for the tumorigenesis of colorectal cancer
Zhang Lin,
Shiyi Yang,
Qianqian Qiu,
Gaoping Cui,
Yanhua Zhang,
Meilian Yao,
Xiangyu Li,
Chengkun Chen,
Jun Gu,
Ting Wang,
Peng Yin,
Longci Sun,
Yujun Hao
Affiliations
Zhang Lin
State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, School of Biomedical Engineering, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200032, China
Shiyi Yang
State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, School of Biomedical Engineering, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200032, China
Qianqian Qiu
State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, School of Biomedical Engineering, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200032, China; Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai, 200433, China
Gaoping Cui
State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, School of Biomedical Engineering, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200032, China
Yanhua Zhang
State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, School of Biomedical Engineering, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200032, China
Meilian Yao
State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, School of Biomedical Engineering, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200032, China
Xiangyu Li
State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, School of Biomedical Engineering, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200032, China
Chengkun Chen
State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, School of Biomedical Engineering, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200032, China
Jun Gu
State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, School of Biomedical Engineering, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200032, China
Ting Wang
State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, School of Biomedical Engineering, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200032, China
Peng Yin
Key Laboratory of Chemical Biology and Traditional Chinese Medicine Research, College of Chemistry and Chemical Engineering, Hunan Normal University, Changsha, 410081, China
Longci Sun
State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, School of Biomedical Engineering, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200032, China; Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China; Corresponding author. Department of Gastrointestinal Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, #160 Pu-Jian Road, Shanghai, 200127, China.
Yujun Hao
State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, School of Biomedical Engineering, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200032, China; Corresponding author. Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Ln2200 #25 Xie-Tu Road, Shanghai, 200032, China
Metabolic reprogramming is a hallmark of human cancer, and cancer-specific metabolism provides opportunities for cancer diagnosis, prognosis, and treatment. However, the underlying mechanisms by which metabolic pathways affect the initiation and progression of colorectal cancer (CRC) remain largely unknown. Here, we demonstrate that cysteine is highly enriched in colorectal tumors compared to adjacent non-tumor tissues, thereby promoting tumorigenesis of CRC. Synchronously importing both cysteine and cystine in colorectal cancer cells is necessary to maintain intracellular cysteine levels. Hypoxia-induced reactive oxygen species (ROS) and ER stress regulate the co-upregulation of genes encoding cystine transporters (SLC7A11, SLC3A2) and genes encoding cysteine transporters (SLC1A4, SLC1A5) through the transcription factor ATF4. Furthermore, the metabolic flux from cysteine to reduced glutathione (GSH), which is critical to support CRC growth, is increased due to overexpression of glutathione synthetase GSS in CRC. Depletion of cystine/cysteine by recombinant cyst(e)inase effectively inhibits the growth of colorectal tumors by inducing autophagy in colorectal cancer cells through mTOR-ULK signaling axis. This study demonstrates the underlying mechanisms of cysteine metabolism in tumorigenesis of CRC, and evaluates the potential of cysteine metabolism as a biomarker or a therapeutic target for CRC.
