Potential therapeutic effect of targeting glycogen synthase kinase 3β in esophageal squamous cell carcinoma
Potential therapeutic effect of targeting glycogen synthase kinase 3β in esophageal squamous cell carcinoma
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DOI：
10.1038/s41598-020-68713-9
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发表时间：
2020-07-16
影响因子：
4.6
通讯作者：
Minamoto, Toshinari
中科院分区：
文献类型：
--
作者：
Bolidong, Dilireba;Domoto, Takahiro;Minamoto, Toshinari
食道鳞状细胞癌(ESCC)是一种常见的胃肠道肿瘤，对现有的治疗方法往往难以奏效。针对食管鳞癌的有效治疗策略的开发是一个重大挑战。糖原合成酶激酶(GSK)3β已成为包括癌症在内的多种疾病的多能治疗靶点。在此，我们研究了GSK3β在ESCC中的生物学和病理作用，并探讨其抑制的治疗作用。GSK3β和酪氨酸(Y)216的磷酸化依赖活性在人ESCC细胞系和原发肿瘤中的表达高于来自ESCC患者的未转化的食管鳞状细胞Tynek-3细胞和癌旁正常食道黏膜。GSK3β特异性抑制剂和小干扰(Si)RNA介导的GSK3β基因敲除抑制了肿瘤细胞的存活和增殖，同时诱导了小鼠ESCC细胞及其异种移植瘤的凋亡。GSK3β的抑制使Tynek-3细胞和小鼠的重要器官免于死亡。抑制GSK3β对肿瘤细胞的治疗作用与G0/G1、G2/M期细胞周期停滞、细胞周期蛋白D1和细胞周期蛋白依赖性激酶(CDK)4表达减少、细胞周期蛋白B1表达增加有关。这些结果表明，GSK3β的促肿瘤作用是通过细胞周期蛋白D1/CDK4介导的细胞周期进程实现的。因此，我们的研究为GSK3β作为ESCC潜在治疗靶点提供了生物学基础。
Esophageal squamous cell carcinoma (ESCC) is a common gastrointestinal cancer and is often refractory to current therapies. Development of efficient therapeutic strategies against ESCC presents a major challenge. Glycogen synthase kinase (GSK)3 beta has emerged as a multipotent therapeutic target in various diseases including cancer. Here we investigated the biology and pathological role of GSK3 beta in ESCC and explored the therapeutic effects of its inhibition. The expression of GSK3 beta and tyrosine (Y)216 phosphorylation-dependent activity was higher in human ESCC cell lines and primary tumors than untransformed esophageal squamous TYNEK-3 cells from an ESCC patient and tumor-adjacent normal esophageal mucosa. GSK3 beta -specific inhibitors and small interfering (si)RNA-mediated knockdown of GSK3 beta attenuated tumor cell survival and proliferation, while inducing apoptosis in ESCC cells and their xenograft tumors in mice. GSK3 beta inhibition spared TYNEK-3 cells and the vital organs of mice. The therapeutic effect of GSK3 beta inhibition in tumor cells was associated with G0/G1- and G2/M-phase cell cycle arrest, decreased expression of cyclin D1 and cyclin-dependent kinase (CDK)4 and increased expression of cyclin B1. These results suggest the tumor-promoting role of GSK3 beta is via cyclin D1/CDK4-mediated cell cycle progression. Consequently, our study provides a biological rationale for GSK3 beta as a potential therapeutic target in ESCC.