Tryptophan Metabolism and Cancer Progression

Abstract

Intracellular tryptophan (Trp) is catabolized to a large repertoire of metabolites via two major pathways: indoleamine and tryptophan 2, 3-dioxygenases (IDO/TDO) and Trp hydroxylase (TPH) pathways. The catabolites possess diverse biological activities and carry out various physiological functions. Several catabolites such as kynurenine (Kyn) and serotonin promote while melatonin and 5-methoxytryptophan (5-MTP) suppress cancer growth and metastasis. Cancer cell-derived Kyn enhances cancer growth and evasion of immunosurveillance by interacting with cancer cell and immune cell membrane aryl hydrocarbon receptors (AHR), respectively. Serotonin exerts its tumorpromoting activities through type 1 and type 2 serotonin receptors. 5-MTP and melatonin suppress cancer growth and metastasis by common mechanisms, i.e., inhibition of p300 histone acetyltransferase (HAT) and NF-κB activation, and suppression of cyclooxygenase-2 and cytokine transcription. Both metabolites block p38 MAPK signaling pathway. Human cancer tissues express increased levels of IDO, TDO and kynurenine monooxygenase (KMO) which are correlated with reduced patient survival. In summary, cancer Trp metabolism regulates cancer growth and metastasis by complex mechanisms. 5-MTP and melatonin provide valuable lead to develop new drugs for chemo-prevention and adjuvant therapy of cancer.