Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, China.
School of Pharmacy, Hubei University of Chinese Medicine, No.16, Huangjiahu Road West, Wuhan, China.
Cell Death Dis. 2020 Apr 20;11(4):248. doi: 10.1038/s41419-020-2471-7.
Sepiapterin reductase plays an enzymatic role in the biosynthesis of tetrahydrobiopterin, which is reported in limited studies to regulate the progression of several tumors. However, the role of sepiapterin reductase in hepatocellular carcinoma remains largely unknown. Here, we found that sepiapterin reductase was frequently highly expressed in human hepatocellular carcinoma, which was significantly associated with higher T stage, higher tumor node metastasis stage, and even shorter survival of hepatocellular carcinoma patients. Furthermore, cell and animal experiments showed that sepiapterin reductase depletion inhibited cancer cell proliferation and promoted cancer cell apoptosis. Importantly, the results suggested that sepiapterin reductase enzymatic activity was not necessary for the progression of hepatocellular carcinoma, based on the comparison between SMMC-7721 and SMMC-7721 containing sepiapterin reductase mutant. Moreover, we showed that sepiapterin reductase regulated the development of hepatocellular carcinoma via the FoxO3a/Bim-signaling pathway. Collectively, our study suggests that sepiapterin reductase controls hepatocellular carcinoma progression via FoxO3a/Bim signaling in a nonenzymatic manner, which provides a potential prognostic factor and therapeutic strategy for hepatocellular carcinoma.
蝶呤还原酶在四氢生物蝶呤的生物合成中发挥酶的作用，有限的研究表明四氢生物蝶呤可调节几种肿瘤的进展。然而，蝶呤还原酶在肝细胞癌中的作用在很大程度上仍不清楚。在这里，我们发现蝶呤还原酶在人肝细胞癌中频繁高度表达，与更高的 T 分期、更高的肿瘤淋巴结转移分期甚至更短的肝细胞癌患者生存期显著相关。此外，细胞和动物实验表明蝶呤还原酶缺失抑制癌细胞增殖并促进癌细胞凋亡。重要的是，结果表明，基于 SMMC-7721 和含有蝶呤还原酶突变体的 SMMC-7721 之间的比较，蝶呤还原酶的酶活性对于肝细胞癌的进展不是必需的。此外，我们表明蝶呤还原酶通过 FoxO3a/Bim 信号通路调节肝细胞癌的发生。总之，我们的研究表明，蝶呤还原酶通过非酶方式通过 FoxO3a/Bim 信号控制肝细胞癌的进展，为肝细胞癌提供了一个潜在的预后因素和治疗策略。
