PTEN公司
硼替佐米
胆囊癌
蛋白酶体抑制剂
生物
癌症研究
蛋白酶体
PI3K/AKT/mTOR通路
癌症
免疫学
遗传学
信号转导
多发性骨髓瘤
作者
Tianyi Jiang,Xiaofan Feng,Fang Zheng,Xiaowen Cui,Yun‐Kai Lin,Yu‐Fei Pan,Chun Yang,Zhiwen Ding,Yongjie Zhang,Yexiong Tan,Hongyang Wang,Liwei Dong
标识
DOI:10.1016/j.canlet.2020.11.016
摘要
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.
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