Targeting Wee1 kinase to suppress proliferation and survival of cisplatin-resistant head and neck squamous cell carcinoma.
Targeting Wee1 kinase to suppress proliferation and survival of cisplatin-resistant head and neck squamous cell carcinoma.
复制标题
靶向 Wee1 激酶抑制顺铂耐药头颈鳞状细胞癌的增殖和存活。
DOI：
10.1007/s00280-022-04410-w
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发表时间：
2022
影响因子：
3
通讯作者：
Dan,Hancai
中科院分区：
文献类型：
--
作者：
Yang,Zejia;Liao,Jipei;Lapidus,RenaG;Fan,Xiaoxuan;Mehra,Ranee;Cullen,KevinJ;Dan,Hancai
目的我们在多种顺铂耐药的 HNSCC 细胞系中研究了 Wee1 激酶在顺铂耐药的头颈鳞状细胞癌 (HNSCC) 中的作用，并确定了 Wee1 抑制剂 AZD1775 单独使用或与顺铂联用对顺铂耐药的 HNSCC 抑制的功效。方法通过蛋白质印迹分析评估细胞的磷酸化和总蛋白水平。分别通过MTS测定和流式细胞术检测细胞活力和凋亡。结果五种顺铂耐药HNSCC细胞类型中Wee1激酶蛋白表达水平高于其亲代顺铂敏感细胞。重要的是，Wee1 敲低抑制了细胞增殖，并使细胞对顺铂治疗重新敏感。有趣的是，之前的研究也表明Wee1抑制剂AZD1775与顺铂具有协同作用，抑制顺铂敏感的HNSCC的细胞增殖。我们发现AZD1775以相似的IC50值抑制顺铂敏感和耐药的HNSCC，这表明AZD1775可以克服顺铂耐药的HNSCC的顺铂耐药性。从机制上讲，AZD1775和顺铂协同诱导DNA损伤和细胞凋亡。结论Wee1抑制剂、AZD1775和顺铂协同抑制HNSCC的增殖和存活。
PurposeWe investigated the role of Wee1 kinase in cisplatin-resistant head and neck squamous cell carcinoma (HNSCC) in multiple cisplatin-resistant HNSCC cell lines and determined the efficacy of either Wee1 inhibitor, AZD1775 alone, or in combination with cisplatin, on cisplatin-resistant HNSCC inhibition.MethodsPhosphorylation and total protein levels of cells were assessed by Western blot analysis. Cell viability and apoptosis were examined by MTS assay and flow cytometry, respectively.ResultsWee1 kinase protein expression levels in five cisplatin-resistant HNSCC cell types were higher than those in their parental cisplatin-sensitive partners. Importantly, Wee1 knockdown inhibited cell proliferation and re-sensitized cells to cisplatin treatment. Interestingly, previous studies have also shown that Wee1 inhibitor AZD1775 synergizes with cisplatin to suppress cell proliferation of cisplatin-sensitive HNSCC. We found that AZD1775 inhibited both cisplatin-sensitive and resistant HNSCC with similar IC50values, which suggested that AZD1775 could overcome cisplatin resistance in cisplatin-resistant HNSCC. Mechanistically, AZD1775 and cisplatin cooperatively induced DNA damage and apoptosis.ConclusionWee1 inhibitor, AZD1775, and cisplatin coordinately suppressed proliferation and survival of HNSCC.