Metabolic reprogramming is a hallmark of human cancer, and cancer-specific metabolism provides opportunities for cancer diagnosis, prognosis, and treatment. However, the underlying mechanisms by which metabolic pathways affect the initiation and progression of colorectal cancer (CRC) remain largely unknown. Here, we demonstrate that cysteine is highly enriched in colorectal tumors compared to adjacent non-tumor tissues, thereby promoting tumorigenesis of CRC. Synchronously importing both cysteine and cystine in colorectal cancer cells is necessary to maintain intracellular cysteine levels. Hypoxia-induced reactive oxygen species (ROS) and ER stress regulate the co-upregulation of genes encoding cystine transporters (SLC7A11, SLC3A2) and genes encoding cysteine transporters (SLC1A4, SLC1A5) through the transcription factor ATF4. Furthermore, the metabolic flux from cysteine to reduced glutathione (GSH), which is critical to support CRC growth, is increased due to overexpression of glutathione synthetase GSS in CRC. Depletion of cystine/cysteine by recombinant cyst(e)inase effectively inhibits the growth of colorectal tumors by inducing autophagy in colorectal cancer cells through mTOR-ULK signaling axis. This study demonstrates the underlying mechanisms of cysteine metabolism in tumorigenesis of CRC, and evaluates the potential of cysteine metabolism as a biomarker or a therapeutic target for CRC.

中文翻译：

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缺氧诱导的半胱氨酸代谢重编程对于结直肠癌的肿瘤发生至关重要


代谢重编程是人类癌症的一个标志，癌症特异性代谢为癌症诊断、预后和治疗提供了机会。然而，代谢途径影响结直肠癌（CRC）发生和进展的潜在机制仍然很大程度上未知。在这里，我们证明，与邻近的非肿瘤组织相比，半胱氨酸在结直肠肿瘤中高度富集，从而促进结直肠癌的肿瘤发生。在结直肠癌细胞中同步输入半胱氨酸和胱氨酸对于维持细胞内半胱氨酸水平是必要的。缺氧诱导的活性氧 (ROS) 和内质网应激通过转录因子 ATF4 共同上调编码胱氨酸转运蛋白 (SLC7A11、SLC3A2) 的基因和编码半胱氨酸转运蛋白 (SLC1A4、SLC1A5) 的基因。此外，由于结直肠癌中谷胱甘肽合成酶 GSS 的过度表达，从半胱氨酸到还原型谷胱甘肽 (GSH) 的代谢通量增加，而谷胱甘肽对支持结直肠癌的生长至关重要。重组胱氨酸/半胱氨酸通过 mTOR-ULK 信号轴诱导结直肠癌细胞自噬，有效抑制结直肠肿瘤的生长。本研究证明了半胱氨酸代谢在结直肠癌肿瘤发生中的潜在机制，并评估了半胱氨酸代谢作为结直肠癌生物标志物或治疗靶点的潜力。