Targeting p38α Increases DNA Damage, Chromosome Instability, and the Anti-tumoral Response to Taxanes in Breast Cancer Cells
Targeting p38α Increases DNA Damage, Chromosome Instability, and the Anti-tumoral Response to Taxanes in Breast Cancer Cells
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DOI：
10.1016/j.ccell.2018.04.010
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发表时间：
2018-06-11
期刊：
影响因子：
50.3
通讯作者：
Nebreda, Angel R.
中科院分区：
文献类型：
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作者：
Canovas, Begona;Igea, Ana;Nebreda, Angel R.
乳腺癌是女性癌症相关死亡的第二大原因。在这里，我们报告了蛋白激酶p38α在协调DNA损伤反应和限制乳腺肿瘤进展过程中染色体不稳定性方面的作用，并确定DNA修复调节因子CtIP为p38α底物。相应地，p38α信号降低导致ATR激活和同源重组修复受损，伴随而来的是复制应激、DNA损伤和染色体不稳定性增加，导致癌细胞死亡和肿瘤消退。此外，我们发现，在小鼠模型和患者来源的异种移植中，对p38α的药理抑制通过增加染色体不稳定性来增强紫杉烷的作用，这表明将p38α抑制剂与导致染色体不稳定的化疗药物相结合具有潜在的兴趣。
Breast cancer is the second leading cause of cancer-related death among women. Here we report a role for the protein kinase p38 alpha in coordinating the DNA damage response and limiting chromosome instability during breast tumor progression, and identify the DNA repair regulator CtIP as a p38 alpha substrate. Accordingly, decreased p38 alpha signaling results in impaired ATR activation and homologous recombination repair, with concomitant increases in replication stress, DNA damage, and chromosome instability, leading to cancer cell death and tumor regression. Moreover, we show that pharmacological inhibition of p38 alpha potentiates the effects of taxanes by boosting chromosome instability in murine models and patient-derived xenografts, suggesting the potential interest of combining p38 alpha inhibitors with chemotherapeutic drugs that induce chromosome instability.