2. Academic Validation
  3. Tryptophan Metabolism Acts as a New Anti-Ferroptotic Pathway to Mediate Tumor Growth

Tryptophan Metabolism Acts as a New Anti-Ferroptotic Pathway to Mediate Tumor Growth

  • Adv Sci (Weinh). 2023 Jan 10;e2204006. doi: 10.1002/advs.202204006.
Dong Liu 1,  Chun-Hui Liang 1,  Bin Huang 2,  Xiao Zhuang 1,  Weiwei Cui 1,  Li Yang 3,  Yinghong Yang 1,  Yudan Zhang 1,  Xiaolong Fu 4,  Xiaoju Zhang 3,  Lutao Du 5,  Wei Gu 6,  Xiangdong Wang 1,  Chengqian Yin 2,  Renjie Chai 4 7 8,  Bo Chu 1
Affiliations

Affiliations

  • 1 Department of Cell Biology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China.
  • 2 Institute for Cancer Research, Shenzhen Bay Laboratory, Shenzhen, 518107, China.
  • 3 Department of Respiratory and Critical Care Medicine, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Zhengzhou University, Zhengzhou, Henan, 450000, China.
  • 4 State Key Laboratory of Bioelectronics, Department of Otolaryngology Head and Neck Surgery, Zhongda Hospital, School of Life Sciences and Technology, Advanced Institute for Life and Health, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, Southeast University, Nanjing, 210096, China.
  • 5 Department of Clinical Laboratory, The Second Hospital of Shandong University, Jinan, Shandong, 250033, China.
  • 6 Institute for Cancer Genetics, and Department of Pathology and Cell Biology, Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, 1130 Nicholas Ave, New York, NY, 10032, USA.
  • 7 Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, 226001, China.
  • 8 Department of Otolaryngology Head and Neck Surgery, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610000, China.
PMID: 36627132 DOI: 10.1002/advs.202204006
Abstract

Emerging evidence reveals that amino acid metabolism plays an important role in ferroptotic cell death. The conversion of methionine to cysteine is well known to protect tumour cells from Ferroptosis upon cysteine starvation through transamination. However, whether amino acids-produced metabolites participate in Ferroptosis independent of the cysteine pathway is largely unknown. Here, the authors show that the tryptophan metabolites serotonin (5-HT) and 3-hydroxyanthranilic acid (3-HA) remarkably facilitate tumour cells to escape from Ferroptosis distinct from cysteine-mediated Ferroptosis inhibition. Mechanistically, both 5-HT and 3-HA act as potent radical trapping antioxidants (RTA) to eliminate lipid peroxidation, thereby inhibiting ferroptotic cell death. Monoamine Oxidase A (MAOA) markedly abrogates the protective effect of 5-HT via degrading 5-HT. Deficiency of MAOA renders Cancer cells resistant to Ferroptosis upon 5-HT treatment. Kynureninase (KYNU), which is essential for 3-HA production, confers cells resistant to ferroptotic cell death, whereas 3-hydroxyanthranilate 3,4-dioxygenase (HAAO) significantly blocks 3-HA mediated Ferroptosis inhibition by consuming 3-HA. In addition, the expression level of HAAO is positively correlated with lipid peroxidation and clinical outcome. Together, the findings demonstrate that tryptophan metabolism works as a new anti-ferroptotic pathway to promote tumour growth, and targeting this pathway will be a promising therapeutic approach for Cancer treatment.

Keywords

3-HA; 3-hydroxyanthranilate 3,4-dioxygenase (HAAO); 5-HT; ferroptosis; kynureninase (KYNU; monoamine oxidase A (MAOA); tryptophan.

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