A positive feedback loop between tryptophan hydroxylase 1 and β-Catenin/ZBP-89 signaling promotes prostate cancer progression

Abstract

Alterations in tryptophan (Trp) metabolism facilitate the continuous modulation of tumor progression, including tumor growth, distant metastasis, and chemoresistance development. Although there is a high correlation between Trp metabolism and tumor progression, it is unknown whether and how Trp metabolism affects the development of prostate cancer. In this study, we reported that the overexpression of Trp hydroxylase 1 (TPH1) caused the upregulation of Trp hydroxylation and mediated the production of 5-hydroxytryptamine (5-HT), contributing to tumor growth and poor prognosis in patients with prostate cancer. An increase in 5-HT levels triggered the activation of the Axin 1/β-catenin signaling pathway, thus enhancing cell proliferation and migration. Consequently, β-catenin cooperated with the Krüppel-type zinc finger family transcription factor ZBP-89 to upregulate TPH1 expression, further promoting Trp hydroxylation and forming the TPH1/5-HT/β-catenin/ZBP-89/THP1 positive feedback signaling loop. Interruption of the signaling loop by the THP1 inhibitor 4-chloro-dl-phenylalanine (PCPA) significantly improved anticancer effects and suppressed lung metastasis in prostate cancer–bearing mice. Our findings revealed a mechanism by which TPH1 promotes prostate cancer growth by inducing Trp hydroxylation and identified a novel THP1 target for an innovative prostate cancer therapeutic strategy.

What should be the future direction of development in the field of prostate cancer with lung metastasis?

“…It has also been reported that the regulation of glutamine metabolism can upregulate ARPC1A in PC cells, resulting in changes in the PC cell cytoskeleton and the cells’ migration and invasion of the lungs[ 79 ]. Furthermore, the regulatory role of the positive feedback loop between tryptophan hydroxylase 1 and β-catenin/ZBP-89 signaling, as well as the modulation of microribonucleic acids in acidosis mediated by the Warburg effect, can enhance the metastatic ability of PC cells[ 80 , 81 ]. These findings indicate a close relationship between organism metabolism and the metastatic behavior of PC cells.…”