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

• Published in: Advanced science 2023-02, Vol.10 (6), p.e2204006-n/a
• Main Authors: Liu, Dong, Liang, Chun‐hui, Huang, Bin, Zhuang, Xiao, Cui, Weiwei, Yang, Li, Yang, Yinghong, Zhang, Yudan, Fu, Xiaolong, Zhang, Xiaoju, Du, Lutao, Gu, Wei, Wang, Xiangdong, Yin, Chengqian, Chai, Renjie, Chu, Bo
• Format: Article
• Language: English
• Subjects: 3‐HA; 3‐hydroxyanthranilate 3,4‐dioxygenase (HAAO); 5‐HT; Amino acids; Apoptosis; Biosynthesis; Cancer; Cells; Cysteine - metabolism; ferroptosis; Humans; kynureninase (KYNU; Lipid Peroxidation; Lipids; Melatonin; Metabolism; Metabolites; monoamine oxidase A (MAOA); Neoplasms - drug therapy; Serotonin; Serotonin - metabolism; tryptophan; Tryptophan - metabolism
• ISSN: 2198-3844; 2198-3844
• DOI: 10.1002/advs.202204006

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. Tryptophan metabolites 5‐HT and 3‐HA act as potent radical trapping antioxidants to inhibit ferroptosis both in vitro and in vivo. Tryptophan metabolites‐mediated ferroptosis suppression is a new anti‐ferroptosis pathway distinct from cysteine‐mediated ferroptosis inhibition or any other classical anti‐ferroptotic pathways to facilitate tumor development. Therefore, targeting this pathway will be a promising therapeutic approach for cancer treatment.