PDF(Pubmed)
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.
摘要：
色氨酸（Trp）代谢的改变促进了肿瘤进展的连续调节，包括肿瘤生长，远处转移,和化学抗性发展。尽管Trp代谢与肿瘤进展之间存在高度相关性，目前尚不清楚Trp代谢是否以及如何影响前列腺癌的发展。在这项研究中,我们报道了Trp羟化酶1（TPH1）的过表达引起Trp羟化的上调，并介导了5-羟色胺（5-HT）的产生，前列腺癌患者的肿瘤生长和不良预后。5-HT水平的增加触发了Axin1/β-catenin信号通路的激活，从而增强细胞增殖和迁移。因此,β-catenin与Krüppel型锌指家族转录因子ZBP-89协同上调TPH1表达,进一步促进Trp羟化并形成TPH1/5-HT/β-catenin/ZBP-89/THP1正反馈信号环。THP1抑制剂4-氯-dl-苯丙氨酸（PCPA）对信号回路的中断显着改善了前列腺癌小鼠的抗癌作用并抑制了肺转移。我们的发现揭示了TPH1通过诱导Trp羟基化促进前列腺癌生长的机制，并为创新的前列腺癌治疗策略确定了新的THP1靶标。
