Institute of Translational Medicine, Nanchang University, Nanchang City, Jiangxi, 330031, China.
School of Life Sciences, Nanchang University, Nanchang City, Jiangxi, 330031, China.
Cell Res. 2018 Jun;28(6):655-669. doi: 10.1038/s41422-018-0021-y. Epub 2018 Mar 7.
Glutamine metabolism plays an important role in cancer development and progression. Glutaminase C (GAC), the first enzyme in glutaminolysis, has emerged as an important target for cancer therapy and many studies have focused on the mechanism of enhanced GAC expression in cancer cells. However, little is known about the post-translational modification of GAC. Here, we report that phosphorylation is a crucial post-translational modification of GAC, which is responsible for the higher glutaminase activity in lung tumor tissues and cancer cells. We identify the key Ser314 phosphorylation site on GAC that is regulated by the NF-κB-PKCε axis. Blocking Ser314 phosphorylation by the S314A mutation in lung cancer cells inhibits the glutaminase activity, triggers genetic reprogramming, and alleviates tumor malignancy. Furthermore, we find that a high level of GAC phosphorylation correlates with poor survival rate of lung cancer patients. These findings highlight a previously unappreciated mechanism for activation of GAC by phosphorylation and demonstrate that targeting glutaminase activity can inhibit oncogenic transformation.
谷氨酰胺代谢在癌症的发生和发展中起着重要作用。谷氨酰胺酶 C（GAC）是谷氨酰胺分解的第一酶，已成为癌症治疗的重要靶点，许多研究集中在癌细胞中增强 GAC 表达的机制上。然而，对于 GAC 的翻译后修饰知之甚少。在这里，我们报告磷酸化是 GAC 的关键翻译后修饰，它负责肺肿瘤组织和癌细胞中更高的谷氨酰胺酶活性。我们确定了 GAC 上受 NF-κB-PKCε 轴调节的关键 Ser314 磷酸化位点。通过在肺癌细胞中 S314A 突变阻断 Ser314 磷酸化可抑制谷氨酰胺酶活性，触发遗传重编程，并减轻肿瘤恶性程度。此外，我们发现 GAC 的高磷酸化水平与肺癌患者的生存率降低相关。这些发现强调了通过磷酸化激活 GAC 的先前未被认识的机制，并表明靶向谷氨酰胺酶活性可以抑制致癌转化。
