Glycine Decarboxylase Activity Drives Non-Small Cell Lung Cancer Tumor-Initiating Cells and Tumorigenesis
Glycine Decarboxylase Activity Drives Non-Small Cell Lung Cancer Tumor-Initiating Cells and Tumorigenesis
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DOI：
10.1016/j.cell.2011.11.050
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发表时间：
2012-01-20
期刊：
影响因子：
64.5
通讯作者：
Lim, Bing
中科院分区：
文献类型：
--
作者：
Zhang, Wen Cai;Shyh-Chang, Ng;Lim, Bing
确定肿瘤起始细胞（TIC）状态的关键因素可能会为癌症治疗开辟新的途径。在这里，我们表明，代谢酶甘氨酸脱羧酶（GLDC）是至关重要的TIC在非小细胞肺癌（NSCLC）。来自原发性NSCLC肿瘤的TIC表达高水平的致癌干细胞因子LIN 28 B和GLDC，这两者都是TIC生长和肿瘤发生所需的。GLDC和其他甘氨酸/丝氨酸酶的过表达，但不是催化失活的GLDC，促进细胞转化和肿瘤发生。我们发现GLDC诱导糖酵解和甘氨酸/丝氨酸代谢的显著变化，导致嘧啶代谢的变化以调节癌细胞增殖。在临床上，GLDC的异常激活与肺癌患者的较差存活率相关，并且在多种癌症类型中观察到异常GLDC表达。甘氨酸代谢和肿瘤发生之间的这种联系可能为推进抗癌治疗提供新的靶点。
Identification of the factors critical to the tumor-initiating cell (TIC) state may open new avenues in cancer therapy. Here we show that the metabolic enzyme glycine decarboxylase (GLDC) is critical for TICs in non-small cell lung cancer (NSCLC). TICs from primary NSCLC tumors express high levels of the oncogenic stem cell factor LIN28B and GLDC, which are both required for TIC growth and tumorigenesis. Overexpression of GLDC and other glycine/serine enzymes, but not catalytically inactive GLDC, promotes cellular transformation and tumorigenesis. We found that GLDC induces dramatic changes in glycolysis and glycine/serine metabolism, leading to changes in pyrimidine metabolism to regulate cancer cell proliferation. In the clinic, aberrant activation of GLDC correlates with poorer survival in lung cancer patients, and aberrant GLDC expression is observed in multiple cancer types. This link between glycine metabolism and tumorigenesis may provide novel targets for advancing anticancer therapy.