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

Hua Ling Chen, Chao Yun Yuan, Huei Hsuan Cheng, Tzu Ching Chang, Shau Ku Huang, Cheng Chin Kuo, Kenneth K. Wu

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)11131-11142
Number of pages12
JournalJournal of Biological Chemistry
Volume293
Issue number28
DOIs
Publication statusPublished - Jan 1 2018

Fingerprint

Acetylserotonin O-Methyltransferase
Tryptophan
Restoration
Protein Isoforms
Cells
Switches
Neoplasms
Transfection
Neoplasm Metastasis
Fibroblasts
Growth
Metabolites
Heterografts
Tumors
Serotonin
Anti-Inflammatory Agents
5-methoxytryptophan
Tissue
Lung
A549 Cells

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Restoration of hydroxyindole O-methyltransferase levels in human cancer cells induces a tryptophan-metabolic switch and attenuates cancer progression. / Chen, Hua Ling; Yuan, Chao Yun; Cheng, Huei Hsuan; Chang, Tzu Ching; Huang, Shau Ku; Kuo, Cheng Chin; Wu, Kenneth K.

In: Journal of Biological Chemistry, Vol. 293, No. 28, 01.01.2018, p. 11131-11142.

Research output: Contribution to journalArticle

Chen, Hua Ling ; Yuan, Chao Yun ; Cheng, Huei Hsuan ; Chang, Tzu Ching ; Huang, Shau Ku ; Kuo, Cheng Chin ; Wu, Kenneth K. / Restoration of hydroxyindole O-methyltransferase levels in human cancer cells induces a tryptophan-metabolic switch and attenuates cancer progression. In: Journal of Biological Chemistry. 2018 ; Vol. 293, No. 28. pp. 11131-11142.
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