Yamauchi Tomoaki, Okano Yumi, Terada Daishu, Yasukochi Sai, Tsuruta Akito, Tsurudome Yuya, Ushijima Kentaro, Matsunaga Naoya, Koyanagi Satoru, Ohdo Shigehiro
Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
Division of Pharmaceutics, Faculty of Pharmaceutical Sciences, Sanyo-Onoda City University, Yamaguchi, Japan.
Cancer Metab. 2024 Aug 7;12(1):23. doi: 10.1186/s40170-024-00352-4.
The metabolic reprogramming of amino acids is critical for cancer cell growth and survival. Notably, intracellular accumulation of cysteine is often observed in various cancers, suggesting its potential role in alleviating the oxidative stress associated with rapid proliferation. The liver is the primary organ for cysteine biosynthesis, but much remains unknown about the metabolic alterations of cysteine and their mechanisms in hepatocellular carcinoma cells.
RNA-seq data from patients with hepatocarcinoma were analyzed using the TNMplot database. The underlying mechanism of the oncogenic alteration of cysteine metabolism was studied in mice implanted with BNL 1ME A.7 R.1 hepatocarcinoma.
Database analysis of patients with hepatocellular carcinoma revealed that the expression of enzymes involved in de novo cysteine synthesis was down-regulated accompanying with increased expression of the cystine uptake transporter xCT. Similar alterations in gene expression have also been observed in a syngeneic mouse model of hepatocarcinoma. The enhanced expression of DNA methyltransferase in murine hepatocarcinoma cells caused methylation of the upstream regions of cysteine synthesis genes, thereby repressing their expression. Conversely, suppression of de novo cysteine synthesis in healthy liver cells induced xCT expression by up-regulating the oxidative-stress response factor NRF2, indicating that reduced de novo cysteine synthesis repulsively increases cystine uptake via enhanced xCT expression, leading to intracellular cysteine accumulation. Furthermore, the pharmacological inhibition of xCT activity decreased intracellular cysteine levels and suppressed hepatocarcinoma tumor growth in mice.
Our findings indicate an underlying mechanism of the oncogenic alteration of cysteine metabolism in hepatocarcinoma and highlight the efficacy of alteration of cysteine metabolism as a viable therapeutic target in cancer.
氨基酸的代谢重编程对癌细胞的生长和存活至关重要。值得注意的是，在各种癌症中经常观察到半胱氨酸在细胞内积累，这表明其在减轻与快速增殖相关的氧化应激方面具有潜在作用。肝脏是半胱氨酸生物合成的主要器官，但关于半胱氨酸在肝癌细胞中的代谢改变及其机制仍有许多未知之处。
使用TNMplot数据库分析肝癌患者的RNA测序数据。在植入BNL 1ME A.7 R.1肝癌的小鼠中研究半胱氨酸代谢致癌改变的潜在机制。
对肝细胞癌患者的数据库分析显示，从头合成半胱氨酸所涉及的酶的表达下调，同时胱氨酸摄取转运蛋白xCT的表达增加。在同基因肝癌小鼠模型中也观察到了类似的基因表达变化。小鼠肝癌细胞中DNA甲基转移酶的表达增强导致半胱氨酸合成基因上游区域的甲基化，从而抑制其表达。相反，在健康肝细胞中抑制从头合成半胱氨酸通过上调氧化应激反应因子NRF2诱导xCT表达，这表明从头合成半胱氨酸的减少通过增强xCT表达反向增加胱氨酸摄取，导致细胞内半胱氨酸积累。此外，对xCT活性的药理学抑制降低了细胞内半胱氨酸水平，并抑制了小鼠肝癌肿瘤的生长。
我们的研究结果揭示了肝癌中半胱氨酸代谢致癌改变的潜在机制，并强调了改变半胱氨酸代谢作为癌症可行治疗靶点的有效性。
