The MASTL-ENSA-PP2A/B55 axis modulates cisplatin resistance in oral squamous cell carcinoma.
The MASTL-ENSA-PP2A/B55 axis modulates cisplatin resistance in oral squamous cell carcinoma.
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DOI：
10.3389/fcell.2022.904719
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发表时间：
2022
影响因子：
5.5
通讯作者：
中科院分区：
文献类型：
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铂类化疗是不能手术、复发或转移的口腔鳞状细胞癌（OSCC）的标准一线治疗。铂敏感性是晚期口腔鳞癌患者生存的主要决定因素。在此，我们研究了MASTL（一种介导ENSA/ARPP 19磷酸化和PP 2A/B55抑制的细胞周期激酶）在OSCC治疗中的作用。有趣的是，MASTL和ENSA/ARPP 19的上调以及PP 2A/B55的下调在OSCC中是常见的。MASTL表达与患者生存率低相关。在已建立的OSCC细胞系中，MASTL和ENSA的上调以及B55基因的下调与顺铂耐药相关。我们进一步证实，MASTL在口腔鳞癌细胞中的稳定表达促进顺铂处理下的细胞存活和增殖，以ENSA依赖的方式。相反，MASTL或ENSA的缺失或B55α的过表达使顺铂反应敏感，这与DNA损伤积累、信号传导和半胱天冬酶活化增加一致。此外，GKI-1，第一类MASTL激酶的小分子抑制剂，在增强顺铂治疗OSCC细胞的结果中表型模仿MASTL消耗，其剂量大大低于破坏有丝分裂进入所需的剂量。最后，GKI-1在小鼠肿瘤异种移植模型中与顺铂治疗联合显示出有希望的疗效。
Platinum-based chemotherapy is the standard first-line treatment for oral squamous cell carcinoma (OSCC) that is inoperable, recurrent, or metastatic. Platinum sensitivity is a major determinant of patient survival in advanced OSCC. Here, we investigated the involvement of MASTL, a cell cycle kinase that mediates ENSA/ARPP19 phosphorylation and PP2A/B55 inhibition, in OSCC therapy. Interestingly, upregulation of MASTL and ENSA/ARPP19, and downregulation of PP2A/B55, were common in OSCC. MASTL expression was in association with poor patient survival. In established OSCC cell lines, upregulation of MASTL and ENSA, and downregulation of B55 genes, correlated with cisplatin resistance. We further confirmed that stable expression of MASTL in OSCC cells promoted cell survival and proliferation under cisplatin treatment, in an ENSA-dependent manner. Conversely, deletion of MASTL or ENSA, or overexpression of B55α, sensitized cisplatin response, consistent with increased DNA damage accumulation, signaling, and caspase activation. Moreover, GKI-1, the first-in-class small molecule inhibitor of MASTL kinase, phenocopied MASTL depletion in enhancing the outcome of cisplatin treatment in OSCC cells, at a dose substantially lower than that needed to disrupt mitotic entry. Finally, GKI-1 exhibited promising efficacy in a mouse tumor xenograft model, in conjunction with cisplatin therapy.