Gouttia Odjo G, Zhao Jing, Li Yanqiu, Zwiener Mackenzie J, Wang Ling, Oakley Gregory G, Peng Aimin
Department of Oral Biology, University of Nebraska Medical Center, Lincoln, NE, United States.
Front Cell Dev Biol. 2022 Sep 28;10:904719. doi: 10.3389/fcell.2022.904719. eCollection 2022.
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.
铂类化疗是不可切除、复发或转移性口腔鳞状细胞癌（OSCC）的标准一线治疗方法。铂敏感性是晚期OSCC患者生存的主要决定因素。在此，我们研究了MASTL（一种介导ENSA/ARPP19磷酸化和PP2A/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/ARPP19的上调以及PP2A/B55的下调在OSCC中很常见。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，在顺铂治疗下，OSCC细胞中MASTL的稳定表达以ENSA依赖的方式促进细胞存活和增殖。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激活增加一致。此外，MASTL激酶的一流小分子抑制剂GKI-1在增强OSCC细胞顺铂治疗效果方面模拟了MASTL缺失，其剂量远低于破坏有丝分裂进入所需的剂量。最后，在小鼠肿瘤异种移植模型中，GKI-1与顺铂联合治疗显示出有前景的疗效。
