Kynurenine Signaling Increases DNA Polymerase Kappa Expression and Promotes Genomic Instability in Glioblastoma Cells.
Kynurenine Signaling Increases DNA Polymerase Kappa Expression and Promotes Genomic Instability in Glioblastoma Cells.
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DOI：
10.1021/acs.chemrestox.5b00452
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发表时间：
2016-01-19
影响因子：
4.1
通讯作者：
Eoff RL
中科院分区：
文献类型：
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作者：
Bostian AC;Maddukuri L;Reed MR;Savenka T;Hartman JH;Davis L;Pouncey DL;Miller GP;Eoff RL
翻译合成聚合酶（TLS pol） hpol κ在胶质母细胞瘤中的过度表达与患者预后不良有关；然而，在这些肿瘤中促进高表达的机制尚不清楚。我们发现，胶质母细胞瘤细胞中芳烃受体（AhR）通路的激活导致hpol κ mRNA和蛋白水平升高。我们使用小分子阻断了AhR在胶质母细胞瘤细胞中的核易位和DNA结合，观察到hpol κ的表达降低。色氨酸-2,3-双加氧酶（TDO）是胶质母细胞瘤中主要负责激活AhR的酶，其药理抑制可导致内源性AhR激动剂犬尿氨酸（Kyn）减少，并相应降低hpol κ蛋白水平。重要的是，我们发现通过RNA干扰抑制TDO活性、AhR信号或抑制hpol κ表达可减少胶质母细胞瘤细胞的染色体损伤。上位性分析进一步支持了TDO活性、AhR信号的激活以及由此产生的hpol κ功能的过表达主要在同一途径中增加内源性DNA损伤的观点。这些发现表明，hpol κ通过胶质母细胞瘤特异性TDO活性的上调和AhR信号的激活可能有助于这些肿瘤中观察到的高水平复制应激和基因组不稳定性。
Over-expression of the translesion synthesis polymerase (TLS pol) hpol κ in glioblastomas has been linked to a poor patient prognosis; however, the mechanism promoting higher expression in these tumors remains unknown. We determined that activation of the aryl hydrocarbon receptor (AhR) pathway in glioblastoma cells leads to increased hpol κ mRNA and protein levels. We blocked nuclear translocation and DNA binding by the AhR in glioblastoma cells using a small-molecule and observed decreased hpol κ expression. Pharmacological inhibition of tryptophan-2,3-dioxygenase (TDO), the enzyme largely responsible for activating the AhR in glioblastomas, led to a decrease in the endogenous AhR agonist kynurenine (Kyn) and a corresponding decrease in hpol κ protein levels. Importantly, we discovered that inhibiting TDO activity, AhR signaling, or suppressing hpol κ expression with RNA interference led to decreased chromosomal damage in glioblastoma cells. Epistasis assays further supported the idea that TDO activity, activation of AhR signaling and the resulting over-expression of hpol κ function primarily in the same pathway to increase endogenous DNA damage. These findings indicate that up-regulation of hpol κ through glioblastoma-specific TDO activity and activation of AhR signaling likely contributes to the high levels of replication stress and genomic instability observed in these tumors.