Activated SIRT1 contributes to DPT-induced glioma cell parthanatos by upregulation of NOX2 and NAT10
Activated SIRT1 contributes to DPT-induced glioma cell parthanatos by upregulation of NOX2 and NAT10
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DOI：
10.1038/s41401-023-01109-3
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发表时间：
2023-06-05
影响因子：
8.2
通讯作者：
Ge，Peng-Fei
中科院分区：
文献类型：
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作者：
Liang，Shi-peng;Wang，Xuan-Zhong;Ge，Peng-Fei
副酒精症是一种依赖于聚腺苷二磷酸核糖聚合酶1(PARP-1)过度激活的程序性细胞死亡。SIRT1是一种高度保守的核脱乙酰酶，经常通过PARP1的脱乙酰基作用作为甲状旁腺激素的抑制因子。我们先前的研究表明，脱氧鬼臼毒素(DPT)是从传统草本植物花椒中分离出来的一种天然化合物，可通过剖腹产引发胶质瘤细胞死亡。在本研究中，我们研究了SIRT1在DPT诱导的人脑胶质瘤细胞恶性转化中的作用。我们发现DPT(450SARPnmo1/L)能激活PARP1SIRT1，并能诱导U87和U251胶质瘤细胞发生恶性转化。SRT2 183(10 μm ol/L)可增强SIRT1的激活，而EX527(200 μm ol/L)抑制SIRT 1或下调SIRT 1可减弱DPT诱导的PARP 1激活和胶质瘤细胞的死亡。我们发现DPT(450nmoL/L)能显著降低U87和U251细胞内 +水平。FK866(100mmoL/L)进一步降低NAD+水平，但补充NAD+(0.5，2 μ /L)可减弱DPT诱导的PARP1I活性。我们发现，NAD+耗竭通过两种途径增强PARP1的活性：一种是通过上调NADPH氧化酶2(NOX2)来加剧依赖ROS的DNA DSB；另一种是通过增加N-乙酰转移酶10(NAT10)的表达来增强PARP1的乙酰化。我们发现，当SIRT1在Ser27位被JNK磷酸化时，SIRT1的活性被提高，反之，激活的SIRT1通过上调ROS相关的ASK1信号而加剧JNK的激活，从而在JNK和SIRT1之间形成正反馈。综上所述，JNK激活的SIRT1通过启动NAD+耗竭依赖的NOX2和NAT10上调，参与了DPT诱导的人脑胶质瘤细胞的甲胎蛋白生成。
Parthanatos is a type of programmed cell death dependent on hyper-activation of poly (ADP-ribose) polymerase 1 (PARP-1). SIRT1 is a highly conserved nuclear deacetylase and often acts as an inhibitor of parthanatos by deacetylation of PARP1. Our previous study showed that deoxypodophyllotoxin (DPT), a natural compound isolated from the traditional herbAnthriscus sylvestris, triggered glioma cell death via parthanatos. In this study, we investigated the role of SIRT1 in DPT-induced human glioma cell parthanatos. We showed that DPT (450 nmol/L) activated both PARP1 and SIRT1, and induced parthanatos in U87 and U251 glioma cells. Activation of SIRT1 with SRT2183 (10 μmol/L) enhanced, while inhibition of SIRT1 with EX527 (200 μmol/L) or knockdown of SIRT1 attenuated DPT-induced PARP1 activation and glioma cell death. We demonstrated that DPT (450 nmol/L) significantly decreased intracellular NAD+levels in U87 and U251 cells. Further decrease of NAD+levels with FK866 (100 μmol/L) aggravated, but supplement of NAD+(0.5, 2 mmol/L) attenuated DPT-induced PARP1 activation. We found that NAD+depletion enhanced PARP1 activation via two ways: one was aggravating ROS-dependent DNA DSBs by upregulation of NADPH oxidase 2 (NOX2); the other was reinforcing PARP1 acetylation via increase of N-acetyltransferase 10 (NAT10) expression. We found that SIRT1 activity was improved when being phosphorylated by JNK at Ser27, the activated SIRT1 in reverse aggravated JNK activation via upregulating ROS-related ASK1 signaling, thus forming a positive feedback between JNK and SIRT1. Taken together, SIRT1 activated by JNK contributed to DPT-induced human glioma cell parthanatos via initiation of NAD+depletion-dependent upregulation of NOX2 and NAT10.