Restoration of hydroxyindole O-methyltransferase levels in human cancer cells induces a tryptophan-metabolic switch and attenuates cancer progression.

Abstract

5-Methoxytryptophan (5-MTP) is a tryptophan metabolite with recently discovered anti-inflammatory and tumor-suppressing activities. Its synthesis is catalyzed by a hydroxyindole O-methyltransferase (HIOMT)-like enzyme. However, the exact identity of this HIOMT in human cells remains unclear. Human HIOMT exists in several alternatively spliced isoforms, and we hypothesized that 5-MTP-producing HIOMT is a distinct isoform. Here, we show that human fibroblasts and cancer cells express the HIOMT298 isoform as contrasted with the expression of the HIOMT345 isoform in pineal cells. Sequencing analysis of the cloned isoforms revealed that HIOMT298 is identical to the sequence of a previously reported truncated HIOMT isoform. Of note, HIOMT298 expression was reduced in cancer cells and tissues. Stable transfection of A549 cancer cells with HIOMT298 restored HIOMT expression to normal levels, accompanied by 5-MTP production. Furthermore, HIOMT298 transfection caused a tryptophan-metabolic switch from serotonin to 5-MTP production. To determine the in vivo relevance of this alteration, we compared growth and lung metastasis of HIOMT298-transfected A549 cells with those of vector- or untransfected A549 cells as controls in a murine xenograft model. Of note, the HIOMT298-transfected A549 cells exhibited slower growth and lower metastasis than the controls. Our findings provide insight into the crucial role of HIOMT298 in 5-MTP production in cells and in inhibiting cancer progression and highlight the potential therapeutic value of 5-MTP for managing cancer.

• Authors: Hua-Ling Chen, Chao-Yun Yuan, Huei-Hsuan Cheng, Tzu-Ching Chang, Shau-Ku Huang, Cheng-Chin Kuo, Kenneth K Wu
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 293 Issue 28 Pg. 11131-11142 (07 13 2018) ISSN: 1083-351X [Electronic] United States
• PMID: 29794137 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• 5-methoxytryptophan
• Serotonin
• Tryptophan
• Acetylserotonin O-Methyltransferase

Topics

• Acetylserotonin O-Methyltransferase (metabolism)
• Animals
• Apoptosis
• Cell Proliferation
• Humans
• Lung Neoplasms (metabolism, pathology)
• Male
• Mice
• Mice, SCID
• Serotonin (metabolism)
• Tryptophan (analogs & derivatives, metabolism)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays