Promotion of ubiquitination-dependent survivin destruction contributes to xanthohumol-mediated tumor suppression and overcomes radioresistance in human oral squamous cell carcinoma
Promotion of ubiquitination-dependent survivin destruction contributes to xanthohumol-mediated tumor suppression and overcomes radioresistance in human oral squamous cell carcinoma
复制标题
促进泛素化依赖性生存素破坏有助于黄腐酚介导的肿瘤抑制并克服人类口腔鳞状细胞癌的放射抗性。
DOI：
10.1186/s13046-020-01593-z
复制
发表时间：
2020-05-14
影响因子：
11.3
通讯作者：
Li, Wei
中科院分区：
文献类型：
--
作者：
Li, Ming;Gao, Feng;Li, Wei
背景生存素的过表达在肿瘤的发生中起着至关重要的作用，并与人类恶性肿瘤的不良预后相关。因此，生存素已被提出作为一个有吸引力的新的抗肿瘤干预措施的目标。方法利用天然产物库，通过MTS法筛选天然化合物。采用贴壁生长分析、免疫印迹、免疫荧光、免疫组化染色、泛素化分析、免疫共沉淀、CRISPR-Cas9基因敲除和异种移植实验等方法，检测口腔鳞状细胞癌（OSCC）中Survivin的表达及黄腐酚（XN）对OSCC的抑制作用。结果Survivin在口腔鳞状细胞癌组织和细胞系中呈高表达。生存素基因的敲除降低了口腔鳞癌细胞在体外和体内的致瘤性。通过天然化合物筛选，我们确定黄腐酚通过降低survivin蛋白水平和激活线粒体凋亡信号来抑制OSCC细胞。黄腐酚抑制Akt-Wee 1-CDK 1信号传导，从而降低Thr 34上的存活素磷酸化，并促进E3连接酶Fbx 17介导的存活素泛素化和降解。黄腐酚单独或与放射联合治疗克服了OSCC异种移植瘤的放射抗性。结论以Survivin为靶点降解Survivin可能是治疗口腔鳞癌的一种有效方法。
Background Overexpression of survivin plays a crucial role in tumorigenesis and correlates with poor prognosis in human malignancies. Thus, survivin has been proposed as an attractive target for new anti-tumor interventions. Methods A natural product library was used for natural compound screening through MTS assay. The expression of survivin in oral squamous cell carcinoma (OSCC) and the inhibitory effect of xanthohumol (XN) on OSCC were examined by anchorage-dependent and -independent growth assays, immunoblot, immunofluorescence, immunohistochemical staining, ubiquitination analysis, co-immunoprecipitation assay, CRISPR-Cas9-based gene knockout, and xenograft experiment. Results Survivin is highly expressed in OSCC patient-derived tissues and cell lines. Knockout of survivin reduced the tumorigenic properties of OSCC cells in vitro and in vivo. With a natural compound screening, we identified that xanthohumol inhibited OSCC cells by reducing survivin protein level and activating mitochondrial apoptotic signaling. Xanthohumol inhibited the Akt-Wee1-CDK1 signaling, which in turn decreased survivin phosphorylation on Thr34, and facilitated E3 ligase Fbxl7-mediated survivin ubiquitination and degradation. Xanthohumol alone or in combination with radiation overcame radioresistance in OSCC xenograft tumors. Conclusion Our findings indicate that targeting survivin for degradation might a promising strategy for OSCC treatment.