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通过抑制 IKKβ 抑制顺铂耐药的头颈部鳞状细胞癌的迁移、侵袭和转移。

Suppression of migration, invasion, and metastasis of cisplatin-resistant head and neck squamous cell carcinoma through IKKβ inhibition.

机构信息

Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.

Department of Pathology, Georgetown University Medical Center, Washington, DC, USA.

出版信息

Clin Exp Metastasis. 2020 Apr;37(2):283-292. doi: 10.1007/s10585-020-10021-7. Epub 2020 Feb 4.

DOI:10.1007/s10585-020-10021-7
PMID:32020377
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7305835/
Abstract

We explored the role of the transcription factor, NF-κB, and its upstream kinase IKKβ in regulation of migration, invasion, and metastasis of cisplatin-resistant head and neck squamous cell carcinoma (HNSCC). We showed that cisplatin-resistant HNSCC cells have a stronger ability to migrate and invade, as well as display higher IKKβ/NF-κB activity compared to their parental partners. Importantly, we found that knockdown of IKKβ, but not NF-κB, dramatically impaired cell migration and invasion in these cells. Consistent with this, the IKKβ inhibitor, CmpdA, also inhibited cell migration and invasion. Previous studies have already shown that N-Cadherin, an epithelial-mesenchymal transition (EMT) marker, and IL-6, a pro-inflammatory cytokine, play important roles in regulation of HNSCC migration, invasion, and metastasis. We found that cisplatin-resistant HNSCC expressed higher levels of N-Cadherin and IL-6, which were significantly inhibited by CmpdA. More importantly, we showed that CmpdA treatment dramatically abated cisplatin-resistant HNSCC cell metastasis to lungs in a mouse model. Our data demonstrated the crucial role of IKKβ in control of migration, invasion, and metastasis, and implicated that targeting IKKβ may be a potential therapy for cisplatin-resistant metastatic HNSCC.

摘要

我们探讨了转录因子 NF-κB 及其上游激酶 IKKβ 在调控顺铂耐药头颈部鳞状细胞癌（HNSCC）迁移、侵袭和转移中的作用。结果表明，与亲本细胞相比，顺铂耐药 HNSCC 细胞具有更强的迁移和侵袭能力，并且 IKKβ/NF-κB 活性更高。重要的是，我们发现 IKKβ 的敲低而非 NF-κB 的敲低显著削弱了这些细胞的迁移和侵袭能力。这与 IKKβ 抑制剂 CmpdA 抑制细胞迁移和侵袭的结果一致。先前的研究已经表明，上皮-间质转化（EMT）标志物 N-钙黏蛋白和促炎细胞因子 IL-6 在调控 HNSCC 迁移、侵袭和转移中起重要作用。我们发现，顺铂耐药 HNSCC 表达更高水平的 N-钙黏蛋白和 IL-6，而 CmpdA 可显著抑制其表达。更重要的是，我们表明 CmpdA 治疗可显著减轻顺铂耐药 HNSCC 细胞在小鼠模型中的肺转移。我们的数据表明 IKKβ 在控制迁移、侵袭和转移中起着至关重要的作用，表明靶向 IKKβ 可能是治疗顺铂耐药转移性 HNSCC 的一种潜在疗法。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5b27/7305835/e7a7a2faa102/nihms-1593000-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5b27/7305835/158c52130c2d/nihms-1593000-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5b27/7305835/61c742ebf554/nihms-1593000-f0002.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5b27/7305835/8fd71211e619/nihms-1593000-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5b27/7305835/ae4e151cf463/nihms-1593000-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5b27/7305835/e7a7a2faa102/nihms-1593000-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5b27/7305835/158c52130c2d/nihms-1593000-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5b27/7305835/61c742ebf554/nihms-1593000-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5b27/7305835/66b36d296260/nihms-1593000-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5b27/7305835/8fd71211e619/nihms-1593000-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5b27/7305835/ae4e151cf463/nihms-1593000-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5b27/7305835/e7a7a2faa102/nihms-1593000-f0006.jpg

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