Yang Zejia, Liao Jipei, Cullen Kevin J, Dan Hancai
1Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD USA.
2Department of Pathology, University of Maryland School of Medicine, Baltimore, MD USA.
Cell Death Discov. 2020 May 15;6:36. doi: 10.1038/s41420-020-0270-7. eCollection 2020.
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.
原癌基因酪氨酸蛋白激酶Src在头颈部鳞状细胞癌（HNSCC）中发挥着重要作用。然而，美国食品药品监督管理局（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，尽管达沙替尼在实验室环境中可以完全抑制Src。这些结果表明，抑制Src会导致其他生存途径的代偿性上调和/或激活，这表明同时靶向Src和潜在的信号通路可能会提高达沙替尼的疗效。在本研究中，我们研究了IKKβ/NF-κB在调节顺铂耐药HNSCC对达沙替尼敏感性中的作用。此外，我们希望确定抑制IKKβ/NF-κB信号通路是否可以在不使用顺铂的情况下增强达沙替尼抑制顺铂耐药HNSCC的疗效。先前的研究表明，ETS-1是一种关键的Src效应蛋白，可调节癌细胞的增殖、抗凋亡和转移。我们发现，达沙替尼抑制Src激酶可降低ETS-1表达，但会导致多种顺铂耐药HNSCC中IKKβ/NF-κB信号的升高。有趣的是，最近鉴定出的IKKβ抑制剂CmpdA（Bay65-1942）抑制IKKβ/NF-κB也导致ETS-1水平降低。此外，敲低IKK而不是NF-κB会显著降低ETS-1表达。此外，在顺铂耐药HNSCC中，IKKβ和ETS-1相互作用。这些数据证明了Src和IKK之间存在相互作用以调节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激活和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HNSCC中起关键作用，同时靶向Src和IKKβ可能是治疗顺铂耐药HNSCC的有效策略。
