Induction of tryptophan hydroxylase in the liver of s.c. tumor model of prostate cancer. Issue 4 (27th February 2020)

• Record Type: Journal Article
• Authors: Hagiwara, Asami; Nakamura, Yoshiyasu; Nishimoto, Rumi; Ueno, Satoko; Miyagi, Yohei
• Is Part Of: Cancer science. Volume 111:Issue 4(2020)
• Page Start: 1218
• Page End: 1227
• Publication Date: 2020-02-27
• Subjects: liver -- mast cell -- serotonin -- tryptophan -- tryptophan hydroxylase; Cancer -- Periodicals; Neoplasms -- Periodicals; Research -- Periodicals; Electronic journals; 616.994005
• DOI: 10.1111/cas.14333
• Languages: English
• ISSNs: 1347-9032

Abstract

Abstract: Enhanced degradation of tryptophan (Trp) and thus decreased plasma Trp levels are common in several types of cancers. Although it is well known that Trp catabolism is induced in the tumor microenvironment by the enzymes expressed in cancer cells, immune cells, or both, few studies have examined systemic Trp catabolism in cancer pathophysiology. The present study aimed to evaluate Trp catabolism in both tumor and peripheral tissues using tumor‐engrafted Copenhagen rats that were s.c. inoculated with AT‐2 rat prostate cancer cells negative for expression of Trp catabolic enzymes. Liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) metabolomics showed significantly decreased plasma Trp levels in AT‐2 engrafted rats, accompanied by increased kynurenine/Trp ratios in spleen and thymus and serotonin levels in liver and thymus. Quantitative PCR and enzymatic activity assays showed indoleamine‐2, 3‐dioxygenase, an inducible enzyme that catalyzes Trp to kynurenine, was increased in tumor tissues, whereas tryptophan‐2, 3‐dioxygenase, a major Trp catabolic enzyme that regulates systemic level of Trp, tended to be increased in the liver of AT‐2 engrafted rats. Furthermore, tryptophan hydroxylase‐1 (TPH1), an enzyme that catalyzes the reaction of Trp to serotonin, was significantly increased in liver and spleen of AT‐2 engrafted rats. Further histochemical analysis revealed that the induction of TPH1 in the liver could be attributed to infiltration of mast cells. A similar phenomenon was observed with nonneoplastic liver samples from colorectal cancer patients. These results suggested that Trp catabolism toward serotonin synthesis might be induced in peripheral remote tissues in cancer, which could have a pathophysiological effect on cancer. Abstract : Our study reported for the first time that L‐tryptophan catabolic enzymes, tryptophan‐2, 3‐dioxygenase (TDO) and/or tryptophan hydroxylase‐1 (TPH1), are induced in remote tissues, liver and spleen, of tumor burden model. Similar TPH1 induction in remote liver tissues was observed with nonneoplastic liver samples from some of the colorectal cancer patients. Our findings suggest that Trp catabolism can be induced not only in tumor microenvironment but also in peripheral remote tisssues in cancer.