2-Oxoadenosine induces cytotoxicity through intracellular accumulation of 2-oxo-ATP and depletion of ATP but not via the p38 MAPK pathway.
2-Oxoadenosine induces cytotoxicity through intracellular accumulation of 2-oxo-ATP and depletion of ATP but not via the p38 MAPK pathway.
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2-氧化丙氨酸通过2-oxo-ATP的细胞内积累和ATP的耗竭诱导细胞毒性，而不是通过p38 MAPK途径诱导细胞毒性。
DOI：
10.1038/s41598-017-06636-8
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发表时间：
2017-07-26
影响因子：
4.6
通讯作者：
Nakabeppu Y
中科院分区：
文献类型：
--
作者：
Asada S;Ohta E;Akimoto Y;Abolhassani N;Tsuchimoto D;Nakabeppu Y
2-氧腺苷 (2-oxo-Ado) 是腺苷的一种氧化形式，具有细胞毒性，可诱导生长停滞和细胞死亡，具有作为抗癌药物的潜力。然而，2-oxo-Ado 如何发挥其细胞毒性尚不清楚。我们检查了 2-oxo-Ado 对非肿瘤细胞（即永生化小鼠胚胎成纤维细胞系）的影响，并研究了 2-oxo-Ado 发挥其细胞毒性的机制。我们发现2-oxo-Ado诱导的细胞死亡是经典的caspase依赖性细胞凋亡，需要腺苷激酶（ADK）和腺苷酸激酶2催化其连续的细胞内磷酸化，导致细胞内2-oxo-ATP的积累，伴随着2-oxo-Ado在RNA中的积累和ATP的耗尽。此外，我们发现MTH1（一种氧化嘌呤核苷三磷酸酶）的过度表达可以防止2-氧代-Ado诱导的细胞毒性，同时抑制细胞内2-氧代-ATP和2-氧代-Ado在RNA中的积累并恢复ATP水平。我们还发现 2-oxo-Ado 激活 p38 MAPK 通路。然而，针对 Mkk3 和 Mkk6 的 siRNA，或用几种 p38 MAPK 抑制剂（SB203580 除外）治疗，并不能阻止细胞毒性。 SB203580 阻止 2-oxo-Ado 细胞内磷酸化为 2-oxo-AMP，体外 ADK 测定显示 SB203580 直接抑制 ADK 活性，表明 SB203580 的部分作用可能依赖于 ADK 抑制。
2-Oxoadenosine (2-oxo-Ado), an oxidized form of adenosine, is cytotoxic and induces growth arrest and cell death, which has potential as an anti-cancer drug. However, it is not well understood how 2-oxo-Ado exerts its cytotoxicity. We examined the effects of 2-oxo-Ado on non-tumour cells, namely immortalized mouse embryonic fibroblast lines, and investigated mechanisms by which 2-oxo-Ado exerts its cytotoxicity. We found that cell death induced by 2-oxo-Ado is classical caspase-dependent apoptosis, and requires its sequential intracellular phosphorylation catalysed by adenosine kinase (ADK) and adenylate kinase 2, resulting in intracellular accumulation of 2-oxo-ATP accompanied by accumulation of 2-oxo-Ado in RNA and depletion of ATP. Moreover, we showed that overexpression of MTH1, an oxidized purine nucleoside triphosphatase, prevents 2-oxo-Ado-induced cytotoxicity accompanied by suppression of accumulation of both intracellular 2-oxo-ATP and 2-oxo-Ado in RNA and recovery of ATP levels. We also found that 2-oxo-Ado activates the p38 MAPK pathway. However, siRNAs against Mkk3 and Mkk6, or treatment with several p38 MAPK inhibitors, except SB203580, did not prevent the cytotoxicity. SB203580 prevented intracellular phosphorylation of 2-oxo-Ado to 2-oxo-AMP, and an in vitro ADK assay revealed that SB203580 directly inhibits ADK activity, suggesting that some of the effects of SB203580 may depend on ADK inhibition.
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DOI：
10.1007/bf02974166
发表时间：
1994-01-01
期刊：
Archives of Pharmacal Research (Seoul)
影响因子：
--
作者：
Lee, Buyean;Kim, Jae Hong;Kong, Jae Yang
通讯作者：
Kong, Jae Yang
影响因子：
5.3
作者：
Ambrosino, C;Mace, G;Nebreda, AR
通讯作者：
Nebreda, AR
影响因子：
56.9
作者：
FUHRMAN, FA;FUHRMAN, GJ;MOSHER, HS
通讯作者：
MOSHER, HS
影响因子：
4.8
作者：
Crawley, JB;Rawlinson, L;Foxwell, BMJ
通讯作者：
Foxwell, BMJ
影响因子：
14.9
作者：
Fujikawa, K;Kamiya, H;Kasai, H
通讯作者：
Kasai, H