谷氨酰胺代谢在细胞恶性转化过程中的作用及其机制研究

It has been recognized that metabolic reprogramming is a core hallmark of cancer. Emerging evidence has been showed that some cancer cells depend primarily on glutamine, a nonessential amino acid, for their growth, proliferation and survival. However, the underlying mechanisms of glutamine dependence of cancer cells in different contexts remain unclear. Here, we show that oncogenic virus Kaposi’s sarcoma-associated herpesvirus (KSHV) upsurges glutamine metabolism of cancer cells by upregulating the expression of numerous critical enzymes including GLS2, GLUD1 and GOT2 to support cell proliferation. Surprisingly, cell crisis is rescued completely only by asparagine but minimally by α-ketoglutarate upon glutamine deprivation, implicating a novel mechanism of glutamine metabolism during the cellular transformation. With these findings, we will further extend our study to chemical and viral carcinogen-transformed cell models and investigate: 1) whether glutamine is required for cellular transformation; 2) the functions of glutamine metabolism during cellular transformation; 3) the molecular mechanisms underlying the regulatory of glutamine metabolism during cellular transformation. The results obtained will disclose the novel mechanisms responsible for cancer metabolism, and provide new molecular targets for developing preventive and therapeutic strategies against specific types of cancer that depend on this pathway.

代谢重塑已被归纳为肿瘤的标志物之一。越来越多证据表明多数肿瘤细胞主要依赖非必需氨基酸谷氨酰胺进行生长、增殖和存活。而在不同背景下肿瘤细胞对谷氨酰胺依赖性的调控机制仍不清楚。我们发现致癌病毒卡波西氏肉瘤相关疱疹病毒（KSHV）通过上调谷氨酰胺代谢通路的关键酶GLS2、GLUD1和GOT2的表达来增强细胞对谷氨酰胺代谢的依赖性。有意思的是，由谷氨酰胺剥夺而造成的细胞生长抑制，只能少量地被TCA代谢中间物α-KG挽救，却能被天冬酰胺完全挽救，提示在细胞恶性转化中谷氨酰胺代谢可能具有新的调控机制。在此基础上，我们拟在化学致癌物和病毒致癌物诱导的细胞恶性转化模型中鉴定：1)谷氨酰胺代谢通路是否影响细胞恶性转化; 2) 谷氨酰胺代谢通路在细胞恶性转化过程中的作用；3）谷氨酰胺代谢通路促进细胞恶性转化的分子机制。这些研究结果将揭示肿瘤代谢的新机制，为谷氨酰胺依赖性的肿瘤的防治提供了新的分子靶点。

代谢重塑被归纳为肿瘤的标志物之一。癌细胞通过重编程细胞代谢途径，以满足其无限增殖所需的各种生物原料和能量。而在细胞恶性转化过程中，这些代谢通路的重塑机制还不十分清楚，特别是谷氨酰胺代谢通路。本项目系统阐述了谷氨酰胺代谢通路在细胞恶性转化过程中的作用及其分子机制，发现致癌病毒KSHV通过重编程谷氨酰胺代谢途径，赋予它核苷酸和非必需氨基酸生物合成的潜力，这些核苷酸和非必需氨基酸对维持细胞合成代谢、增殖、以及KSHV诱导的细胞转化至关重要。而谷氨酰胺的高速消耗通常与瓜氨酸—一氧化氮（NO）循环相结合。在KSHV恶性转化细胞中，KSHV通过多种microRNA上调瓜氨酸—NO循环中的关键酶ASS1的表达，调节细胞内NO水平并介导STAT3通路的激活，从而促进细胞的增殖和恶性转化。同时，我们还发现了一些新型分子在细胞代谢和肿瘤进展中的作用：短肽MPM调节线粒体代谢促进成肌细胞的分化；长非编码RNA lnc-UCID和PDIA3P1在肝癌中的表达上调导致其调控的信号通路失控，从而赋予细胞无限增殖及抵抗凋亡的能力。上述研究结果揭示了肿瘤代谢调控的新机制，为抗肿瘤治疗提供了新靶点。