RSK promotes G2 DNA damage checkpoint silencing and participates in melanoma chemoresistance
RSK promotes G2 DNA damage checkpoint silencing and participates in melanoma chemoresistance
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DOI：
10.1038/onc.2012.472
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发表时间：
2013-09-19
期刊：
影响因子：
8
通讯作者：
Roux, P. P.
中科院分区：
文献类型：
--
作者：
Ray-David, H.;Romeo, Y.;Roux, P. P.
恶性黑色素瘤的发病率在全球范围内迅速增长，并且仍然没有针对转移性疾病的有效治疗方法。这种类型的癌症对传统的 DNA 损伤性化疗药物具有高度耐药性，并且大量研究致力于了解化疗耐药性背后的分子途径。 Ras/丝裂原激活蛋白激酶 (MAPK) 信号通路在黑色素瘤中经常失调，通常含有 NRAS 或 BRAF 的激活突变。在此，我们证明 MAPK 激活的蛋白激酶 RSK（p90 核糖体 S6 激酶）通过改变黑色素瘤对化疗药物的反应而导致黑色素瘤化疗耐药。我们发现，在体外和体内，RSK 都会在抑制位点 Ser280 处磷酸化检查点激酶 1 (Chk1)。我们的结果表明，RSK 是在 Ras/MAPK 途径的有丝分裂原和癌基因下游起作用的主要蛋白激酶，与此一致，我们发现 RSK 在黑色素瘤中持续磷酸化 Chk1。我们发现 RSK 抑制会增加 Chk1 对 DNA 损伤剂的反应活性，这表明 Ras/MAPK 途径调节 Chk1 功能和对 DNA 损伤的反应。因此，我们证明 RSK 以 Chk1 依赖性方式促进 G2 DNA 损伤检查点沉默，并发现 RSK 抑制剂使黑色素瘤细胞对 DNA 损伤剂敏感。总之，我们的结果确定了 Ras/MAPK 通路与 DNA 损伤反应之间的新联系，并表明 RSK 抑制剂可用于调节化疗敏感性，这是黑色素瘤治疗的主要障碍之一。
The incidence of malignant melanoma is growing rapidly worldwide and there is still no effective therapy for metastatic disease. This type of cancer is highly resistant to conventional DNA-damaging chemotherapeutics, and intense research has been dedicated for understanding the molecular pathways underlying chemoresistance. The Ras/mitogen-activated protein kinase (MAPK) signalling pathway is often deregulated in melanoma, which frequently harbours activating mutations in NRAS or BRAF. Herein, we demonstrate that the MAPK-activated protein kinase RSK (p90 ribosomal S6 kinase) contributes to melanoma chemoresistance by altering their response to chemotherapeutic agents. We find that RSK phosphorylates checkpoint kinase 1 (Chk1) at an inhibitory site, Ser280, both in vitro and in vivo. Our results indicate that RSK is the predominant protein kinase operating downstream of mitogens and oncogenes of the Ras/MAPK pathway, and consistent with this, we find that RSK constitutively phosphorylates Chk1 in melanoma. We show that RSK inhibition increases Chk1 activity in response to DNA-damaging agents, suggesting that the Ras/MAPK pathway modulates Chk1 function and the response to DNA damage. Accordingly, we demonstrate that RSK promotes G2 DNA damage checkpoint silencing in a Chk1-dependent manner, and find that RSK inhibitors sensitize melanoma cells to DNA-damaging agents. Together, our results identify a novel link between the Ras/MAPK pathway and the DNA damage response, and suggest that RSK inhibitors may be used to modulate chemosensitivity, which is one of the major obstacles to melanoma treatment.