Inhibition of IKKβ/NF-κB signaling pathway to improve Dasatinib efficacy in suppression of cisplatin-resistant head and neck squamous cell carcinoma.
Inhibition of IKKβ/NF-κB signaling pathway to improve Dasatinib efficacy in suppression of cisplatin-resistant head and neck squamous cell carcinoma.
复制标题
抑制 IKKβ/NF-κB 信号通路可提高达沙替尼抑制顺铂耐药头颈鳞状细胞癌的疗效。
DOI：
10.1038/s41420-020-0270-7
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发表时间：
2020
影响因子：
7
通讯作者：
Dan,Hancai
中科院分区：
文献类型：
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作者：
Yang,Zejia;Liao,Jipei;Cullen,KevinJ;Dan,Hancai
原癌基因酪氨酸蛋白激酶Src在头颈部鳞状细胞癌中起重要作用。然而，FDA批准的SRC抑制剂达沙替尼在HNSCC临床试验中显示出非常有限的疗效，尽管达沙替尼可以在实验室环境中完全抑制SRC。这些结果表明，SRC抑制可引起其他存活通路的代偿性上调和/或激活，这表明SRC和潜在信号通路的共靶向可能改善达沙替尼的疗效。本研究探讨IKKβ/NF-κB在顺铂耐药HNSCC对达沙替尼敏感性调节中的作用。此外，我们希望确定在不使用顺铂的情况下，抑制IKKβ/NF-κB信号通路是否可以增强达沙替尼抑制顺铂耐药HNSCC的疗效。以前的研究表明，ETS-1是一个重要的SRC效应蛋白，调节癌细胞增殖，抗凋亡和转移。我们发现，达沙替尼抑制SRC激酶可降低ETS-1的表达，但可导致多发性顺铂耐药HNSCC中IKKβ/NF-κB信号的升高。有趣的是，最近发现的IKKβ抑制剂CmpdA（Bay 65 -1942）抑制IKKβ/NF-κB也导致ETS-1水平降低。此外，IKK的敲低，而不是NF-κB，显着降低ETS-1的表达。此外，IKKβ和ETS-1在顺铂耐药的HNSCC中相互作用。这些数据表明SRC和IKK之间的相互作用调节NF-κB和ETS-1。此外，我们发现通过达沙替尼和CmpdA联合同时抑制SRC和IKKβ可协同抑制NF-κB活化和ETS-1表达，抑制细胞增殖并诱导凋亡。综上所述，我们的数据表明SRC和IKKβ在顺铂耐药的HNSCCC中起关键作用，并且联合靶向SRC和IKKβ可能是治疗顺铂耐药的HNSCC的有效策略。
Proto-oncogene tyrosine-protein kinase Src plays an important role in Head and Neck Squamous Cell Carcinoma (HNSCC). However, the FDA-approved SRC inhibitor Dasatinib shows very limited efficacy in HNSCC clinical trials, even though Dasatinib can completely inhibit SRC in the laboratory setting. These results suggest that SRC inhibition can cause compensatory up-regulation and/or activation of other survival pathways, which suggests that co-targeting of SRC and the potential signaling pathways may improve the Dasatinib efficacy. In this study, we investigated the role of IKKβ/NF-κB in regulation of the sensitivity of cisplatin-resistant HNSCC to Dasatinib. Additionally, we wished to determine whether inhibition of the IKKβ/NF-κB signaling pathway could enhance Dasatinib efficacy to inhibit cisplatin-resistant HNSCC without the use of cisplatin. Previous studies have shown that ETS-1 is a crucial SRC effector protein that regulates cancer cell proliferation, anti-apoptosis, and metastasis. We found that SRC kinase inhibition by Dasatinib decreased ETS-1 expression but caused elevation of IKKβ/NF-κB signaling in multiple cisplatin-resistant HNSCC. Interestingly, inhibition of IKKβ/NF-κB by CmpdA (Bay65-1942), a recently identified IKKβ inhibitor, also led to a decrease in ETS-1 levels. Moreover, the knockdown of IKK, but not NF-κB, dramatically decreased ETS-1 expression. In addition, IKKβ and ETS-1 interacted in cisplatin-resistant HNSCC. These data demonstrated cross-talk between SRC and IKK to regulate NF-κB and ETS-1. Furthermore, we found that simultaneous inhibition of SRC and IKKβ through a Dasatinib and CmpdA combination synergistically inhibited NF-κB activation and ETS-1expression, suppressed cell proliferation, and induced apoptosis. Taken together, our data indicate that SRC and IKKβ play crucial roles in cisplatin-resistant HNSCCC and co-targeting SRC and IKKβ could be an effective strategy to treat cisplatin-resistant HNSCC.