Inhibition of the mitogen activated protein (MAP) kinase cascade potentiates cell killing by low dose ionizing radiation in A431 human squamous carcinoma cells
Inhibition of the mitogen activated protein (MAP) kinase cascade potentiates cell killing by low dose ionizing radiation in A431 human squamous carcinoma cells
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DOI：
10.1038/sj.onc.1201802
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发表时间：
1998-05-28
期刊：
影响因子：
8
通讯作者：
Dent, P
中科院分区：
文献类型：
--
作者：
Carter, S;Auer, KL;Dent, P
肿瘤细胞在电离辐射照射后存活的分子机制尚不完全清楚。A431细胞暴露于低剂量辐射（1Gy）下，可延长丝裂原活化蛋白（MAP）激酶和应激活化蛋白（SAP）激酶途径的激活，并通过MAP激酶依赖机制诱导p21（Cip-1/WAF1）。相比之下，较高剂量的辐射（6 Gy）导致MAP激酶级联的激活弱得多，但SAP激酶级联的激活程度相似。在MAP激酶封锁的特定MEK1抑制剂(PD98059)的基底活动SAP激酶途径增强双重的,和的能力1 Gy辐射激活SAP激酶途径增加类似于6倍60分钟照射后,在MAP激酶由PD98059封锁的能力一个1 Gy接触导致双链DNA断裂(TUNEL分析)在以下24-48h至少提高三倍。在辐射暴露后的4-8天内，通过MTT试验判断，48小时内DNA损伤的增加也反映在A431细胞生长的类似下降上。本报告表明，MAP激酶级联是A431人鳞状癌细胞的关键细胞保护通路，在临床使用的电离辐射剂量下被激活，抑制该通路可增强低剂量辐射暴露诱导细胞体外死亡的能力。
The molecular mechanism(s) by which tumor cells survive after exposure to ionizing radiation are not fully understood. Exposure of A431 cells to low doses of radiation (1Gy) caused prolonged activations of the mitogen activated protein (MAP) kinase and stress activated protein (SAP) kinase pathways, and induced p21(Cip-1/WAF1) via a MAP kinase dependent mechanism. In contrast, higher doses of radiation (6 Gy) caused a much weaker activation of the MAP kinase cascade, but a similar degree of SAP kinase cascade activation. In the presence of MAP kinase blockade by the specific MEK1 inhibitor (PD98059) the basal activity of the SAP kinase pathway was enhanced twofold, and the ability of a 1 Gy radiation exposure to activate the SAP kinase pathway was increased similar to sixfold 60 min after irradiation, In the presence of MAP kinase blockade by PD98059 the ability of a single 1Gy exposure to cause double stranded DNA breaks (TUNEL assay) was enhanced at least threefold over the following 24-48h. The increase in DNA damage within 48 h was also mirrored by a similar decrease in A431 cell growth as judged by MTT assays over the next 4-8 days following radiation exposure. This report demonstrates that the MAP kinase cascade is a key cytoprotective pathway in A431 human squamous carcinoma cells which is activated in response to clinically used doses of ionizng radiation, Inhibition of this pathway potentiates the ability of low dose radiation exposure to induce cell death im vitro.