PTEN deficiency facilitates the therapeutic vulnerability to proteasome inhibitor bortezomib in gallbladder cancer

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
出处
期刊:Cancer Letters [Elsevier]
卷期号:501: 187-199 被引量:12
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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