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首页> 外文期刊>Cancer biology & therapy >ZAK is required for doxorubicin, a novel ribotoxic stressor, to induce SAPK activation and apoptosis in HaCaT cells.
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ZAK is required for doxorubicin, a novel ribotoxic stressor, to induce SAPK activation and apoptosis in HaCaT cells.

机译：ZAK是阿霉素（一种新型的核毒性应激物）所必需的，以诱导HaCaT细胞中SAPK活化和凋亡。

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摘要

Doxorubicin is an anthracycline drug that is one of the most effective and widely used anticancer agents for the treatment of both hematologic and solid tumors. The stress-activated protein kinases (SAPKs) are frequently activated by a number of cancer chemotherapeutics. When phosphorylated, the SAPKs initiate a cascade that leads to the production of proinflammatory cytokines. Some inhibitors of protein synthesis, known as ribotoxic stressors, coordinately activate SAPKs and lead to apoptotic cell death. We demonstrate that doxorubicin effectively inhibits protein synthesis, activates SAPKs, and causes apoptosis. Ribotoxic stressors share a common mechanism in that they require ZAK, an upstream MAP3K, to activate the pro-apoptotic and proinflammatory signaling pathways that lie downstream of SAPKs. By employing siRNA mediated knockdown of ZAK or administration of sorafenib and nilotinib, kinase inhibitors that have a high affinity for ZAK, we provide evidence that ZAK is required for doxorubicin-induced proinflammatory and apoptotic responses in HaCaT cells, a pseudo-normal keratinocyte cell line, but not in HeLa cells, a cancerous cell line. ZAK has two different isoforms, ZAK-alpha (91 kDa) and ZAK-beta (51 kDa). HaCaT or HeLa cells treated with doxorubicin and immunoblotted for ZAK displayed a progressive decrease in the ZAK-alpha band and the appearance of ZAK-beta bands of larger size. Abrogation of these changes after exposure of cells to sorafenib and nilotinib suggests that these alterations occur following stimulation of ZAK. We suggest that ZAK inhibitors such as sorafenib or nilotinib may be effective when combined with doxorubicin to treat cancer patients.
机译：阿霉素是一种蒽环类药物，是治疗血液肿瘤和实体瘤的最有效和广泛使用的抗癌药之一。应力激活的蛋白激酶（SAPKs）经常被多种癌症化学疗法激活。当磷酸化时，SAPKs启动级联反应，从而导致促炎细胞因子的产生。一些蛋白质合成抑制剂（称为核糖毒性应激源）可协同激活SAPKs并导致凋亡性细胞死亡。我们证明阿霉素有效抑制蛋白质合成，激活SAPKs，并引起细胞凋亡。核毒性应激源共有一个共同的机制，即它们需要ZAK（上游MAP3K）来激活SAPKs下游的促凋亡和促炎性信号通路。通过采用siRNA介导的ZAK敲除或对索拉非尼和尼洛替尼（对ZAK具有高亲和力的激酶抑制剂）进行管理，我们提供了证据证明ZAK是阿霉素诱导的假正常角质形成细胞系HaCaT细胞中促炎和凋亡反应所必需的，但在癌细胞系HeLa细胞中却没有。 ZAK具有两种不同的同工型，ZAK-α（91 kDa）和ZAK-β（51 kDa）。用阿霉素处理并进行ZAK免疫印迹的HaCaT或HeLa细胞显示ZAK-α条带逐渐减少，并出现了较大尺寸的ZAK-β条带。将细胞暴露于索拉非尼和尼洛替尼后，这些变化的消除表明这些变化在刺激ZAK之后发生。我们建议Z​​AK抑制剂（如索拉非尼或尼洛替尼）与阿霉素联合治疗癌症患者时可能有效。

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