PTEN deficiency facilitates the therapeutic vulnerability to proteasome inhibitor bortezomib in gallbladder cancer
PTEN deficiency facilitates the therapeutic vulnerability to proteasome inhibitor bortezomib in gallbladder cancer
复制标题
PTEN 缺乏导致胆囊癌中蛋白酶体抑制剂硼替佐米的治疗脆弱性。
DOI：
10.1016/j.canlet.2020.11.016
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发表时间：
2021-01-25
期刊：
影响因子：
9.7
通讯作者：
Dong, Li-Wei
中科院分区：
文献类型：
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作者：
Jiang, Tian-Yi;Feng, Xiao-Fan;Dong, Li-Wei
胆囊癌是一种侵袭性强、预后差的胆道恶性肿瘤。尽管一些研究已经显示了相关遗传改变的频率，但在精准医学时代，很少有遗传模型或转化研究真正有益于GBC治疗。通过靶向测序和免疫组化染色，我们发现GBC标本中第十号染色体磷酸盐和张力同源性缺失（PTEN）经常发生改变，并且PTEN表达缺失与不良生存结局独立相关。进一步的药物筛选试验显示，蛋白酶体抑制剂硼替佐米是一种有前途的GBC治疗药物，PTEN的敲低增加了硼替佐米在体内和体外的疗效。患者来源的异种移植物（PDX）的治疗评价强烈支持硼替佐米在PTEN缺陷GBC中的利用。机械上，功能性PTEN抑制ARE依赖性转录活性，相同的机制调节蛋白酶体亚基的转录，因此PTEN抑制蛋白酶体活性和硼替佐米敏感性。通过siRNA筛选，我们鉴定了ARE相关的转录抑制因子BACH 1，其参与了PTEN介导的蛋白酶体抑制，并受PTEN-AKT 1轴调控。总之，我们的研究表明，蛋白酶体活性是PTEN缺陷GBC肿瘤的主要治疗靶点，值得进一步临床验证。
Gallbladder cancer (GBC) is an aggressive malignancy of biliary tract with poor prognosis. Although several studies have shown the frequency of relevant genetic alterations, there are few genetic models or translational studies that really benefit for GBC treatment in the era of precision medicine. By targeted sequencing and immunohistochemistry staining, we identified that phosphate and tension homology deleted on chromosome ten (PTEN) was frequently altered in GBC specimens, and loss of PTEN expression was independently correlated with poor survival outcomes. Further drug screening assays revealed proteasome inhibitor bortezomib as a promising agent for GBC treatment, and knockdown of PTEN increased bortezomib efficacy both in vivo and in vitro. Therapeutic evaluation of patient derived xenografts (PDXs) strongly supported the utilization of bortezomib in PTEN deficient GBC. Mechanically, functional PTEN inhibited ARE-dependent transcriptional activity, the same machinery regulating the transcription of proteasome subunits, thus PTEN suppressed proteasome activity and bortezomib sensitivity. Through siRNA screening, we identified the ARE-related transcriptional suppressor BACH1 involved in PTEN-mediated proteasome inhibition and regulated by PTEN-AKT1 axis. In summary, our study indicates that proteasome activity represents a prime therapeutic target in PTEN-deficient GBC tumors, which is worthy of further clinical validation.