ATF3-CBS signaling axis coordinates ferroptosis and tumorigenesis in colorectal cancer
Junjia Liu,
Xinyi Lu,
Siyu Zeng,
Rong Fu,
Xindong Wang,
Lingtao Luo,
Ting Huang,
Xusheng Deng,
Hualei Zheng,
Shaoqian Ma,
Dan Ning,
Lili Zong,
Shu-Hai Lin,
Yongyou Zhang
Affiliations
Junjia Liu
State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, Engineering Research Centre of Molecular Diagnostics of the Ministry of Education, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China
Xinyi Lu
State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, Engineering Research Centre of Molecular Diagnostics of the Ministry of Education, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China
Siyu Zeng
State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, Engineering Research Centre of Molecular Diagnostics of the Ministry of Education, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China
Rong Fu
State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, Engineering Research Centre of Molecular Diagnostics of the Ministry of Education, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China
Xindong Wang
State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, Engineering Research Centre of Molecular Diagnostics of the Ministry of Education, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China
Lingtao Luo
Department of Gastrointestinal Surgery, The First Affiliated Hospital of Xiamen University, Xiamen University, Xiamen, Fujian, 361102, China
Ting Huang
State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, Engineering Research Centre of Molecular Diagnostics of the Ministry of Education, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China; School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian, 361102, China
Xusheng Deng
State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, Engineering Research Centre of Molecular Diagnostics of the Ministry of Education, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China
Hualei Zheng
State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, Engineering Research Centre of Molecular Diagnostics of the Ministry of Education, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China
Shaoqian Ma
State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, Engineering Research Centre of Molecular Diagnostics of the Ministry of Education, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China
Dan Ning
State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, Engineering Research Centre of Molecular Diagnostics of the Ministry of Education, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China
Lili Zong
School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian, 361102, China
Shu-Hai Lin
State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, Engineering Research Centre of Molecular Diagnostics of the Ministry of Education, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China; National Institute for Data Science in Health and Medicine Engineering, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China
Yongyou Zhang
State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, Engineering Research Centre of Molecular Diagnostics of the Ministry of Education, School of Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China; National Institute for Data Science in Health and Medicine Engineering, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China; Corresponding author. School of Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China.
The induction of ferroptosis is promising for cancer therapy. However, the mechanisms enabling cancer cells to evade ferroptosis, particularly in low-cystine environments, remain elusive. Our study delves into the intricate regulatory mechanisms of Activating transcription factor 3 (ATF3) on Cystathionine β-synthase (CBS) under cystine deprivation stress, conferring resistance to ferroptosis in colorectal cancer (CRC) cells. Additionally, our findings establish a positively correlation between this signaling axis and CRC progression, suggesting its potential as a therapeutic target. Mechanistically, ATF3 positively regulates CBS to resist ferroptosis under cystine deprivation stress. In contrast, the suppression of CBS sensitizes CRC cells to ferroptosis through targeting the mitochondrial tricarboxylic acid (TCA) cycle. Notably, our study highlights that the ATF3-CBS signaling axis enhances ferroptosis-based CRC cancer therapy. Collectively, the findings reveal that the ATF3-CBS signaling axis is the primary feedback pathway in ferroptosis, and blocking this axis could be a potential therapeutic approach for colorectal cancer.
