Marlene and Stewart Greenebaum Comprehensive Cancer Center, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
Department of Anesthesiology, University of Maryland, Baltimore, MD, 21201, USA.
Sci Rep. 2020 Dec 3;10(1):21159. doi: 10.1038/s41598-020-78193-6.
Inactivation of Ataxia-telangiectasia mutated (ATM) gene results in an increased risk to develop cancer. We show that ATM deficiency in diffuse large B-cell lymphoma (DLBCL) significantly induce mitochondrial deacetylase sirtuin-3 (SIRT3) activity, disrupted mitochondrial structure, decreased mitochondrial respiration, and compromised TCA flux compared with DLBCL cells expressing wild type (WT)-ATM. This corresponded to enrichment of glutamate receptor and glutamine pathways in ATM deficient background compared to WT-ATM DLBCL cells. ATM DLBCL cells have decreased apoptosis in contrast to radiosensitive non-cancerous A-T cells. In vivo studies using gain and loss of SIRT3 expression showed that SIRT3 promotes growth of ATM CRISPR knockout DLBCL xenografts compared to wild-type ATM control xenografts. Importantly, screening of DLBCL patient samples identified SIRT3 as a putative therapeutic target, and validated an inverse relationship between ATM and SIRT3 expression. Our data predicts SIRT3 as an important therapeutic target for DLBCL patients with ATM null phenotype.
突变型共济失调毛细血管扩张症基因（ATM）失活会增加罹患癌症的风险。我们发现，弥漫性大 B 细胞淋巴瘤（DLBCL）中 ATM 缺陷会显著诱导线粒体去乙酰化酶沉默调节蛋白 3（SIRT3）活性，破坏线粒体结构，降低线粒体呼吸，并损害三羧酸循环（TCA）通量，而表达野生型 ATM（WT-ATM）的 DLBCL 细胞则不会。与 WT-ATM DLBCL 细胞相比，这种情况对应于 ATM 缺陷背景中谷氨酸受体和谷氨酰胺途径的富集。与对放射线敏感的非癌细胞 A-T 细胞相比，ATM DLBCL 细胞的细胞凋亡减少。使用 SIRT3 表达的获得和缺失的体内研究表明，与野生型 ATM 对照异种移植物相比，SIRT3 促进 ATM CRISPR 敲除的 DLBCL 异种移植物的生长。重要的是，对 DLBCL 患者样本的筛选确定 SIRT3 是一个潜在的治疗靶点，并验证了 ATM 和 SIRT3 表达之间的反比关系。我们的数据预测 SIRT3 是 ATM 缺失表型的 DLBCL 患者的重要治疗靶点。
