Department of Biochemistry, Institute for Aging and Metabolic Diseases, College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea.
Institute for Aging and Metabolic Diseases, College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea.
Cell Death Dis. 2018 Jan 19;9(2):55. doi: 10.1038/s41419-017-0089-1.
Cellular senescence, which leads to a cell cycle arrest of damaged or dysfunctional cells, is an important mechanism to restrain the malignant progression of cancer cells. Because metabolic changes underlie many cell-fate decisions, it has been suggested that cell metabolism might play key roles in senescence pathways. Here, we show that mitochondrial glutamine metabolism regulates senescence in human pancreatic ductal adenocarcinoma (PDAC) cells. Glutamine deprivation or inhibition of mitochondrial aspartate transaminase (GOT2) results in a profound induction of senescence and a suppression of PDAC growth. Glutamine carbon flow through GOT2 is required to create NADPH and to maintain the cellular redox state. We found that elevated reactive oxygen species levels by GOT2 knockdown lead to the cyclin-dependent kinase inhibitor p27-mediated senescence. Importantly, PDAC cells exhibit distinct dependence on this pathway, whereas knockdown of GOT2 did not induce senescence in non-transformed cells. The essentiality of GOT2 in senescence regulation of PDAC, which is dispensable in their normal counterparts, may have profound implications for the development of strategies to treat these refractory cancers.
细胞衰老会导致受损或功能失调细胞的细胞周期停滞，是抑制癌细胞恶性进展的重要机制。由于代谢变化是许多细胞命运决定的基础，因此有人提出细胞代谢可能在衰老途径中发挥关键作用。在这里，我们表明线粒体谷氨酰胺代谢调节人胰腺导管腺癌（PDAC）细胞的衰老。谷氨酰胺剥夺或抑制线粒体天冬氨酸转氨酶（GOT2）会导致衰老的强烈诱导和 PDAC 生长的抑制。GOT2 通过谷氨酰胺碳流产生 NADPH 并维持细胞氧化还原状态。我们发现 GOT2 敲低导致活性氧水平升高，从而引发 cyclin 依赖性激酶抑制剂 p27 介导的衰老。重要的是，PDAC 细胞对这条途径表现出明显的依赖性，而 GOT2 的敲低不会诱导非转化细胞衰老。GOT2 在 PDAC 衰老调控中的必要性，在其正常对应物中是可有可无的，这可能对开发治疗这些难治性癌症的策略具有深远的意义。
