PTEN deficiency facilitates the therapeutic vulnerability to proteasome inhibitor bortezomib in gallbladder cancer. (31st March 2021)

• Record Type: Journal Article
• Authors: Jiang, Tian-Yi; Feng, Xiao-Fan; Fang, Zheng; Cui, Xiao-Wen; Lin, Yun-Kai; Pan, Yu-Fei; Yang, Chun; Ding, Zhi-Wen; Zhang, Yong-Jie; Tan, Ye-Xiong; Wang, Hong-Yang; Dong, Li-Wei
• Is Part Of: Cancer letters. Volume 501(2021)
• Page Start: 187
• Page End: 199
• Publication Date: 2021-03-31
• Subjects: Gallbladder cancer -- PTEN -- Bortezomib -- Proteasome -- BACH1; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2020.11.016
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: 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. Highlights: Loss of PTEN is common and independently correlated with poor outcomes of GBC patients. PTEN deficiency increases the efficacy of proteasome inhibitor bortezomib both in vivo and in vitro. Therapeutic evaluation of PDXs strongly supports the utilization of bortezomib in PTEN deficient GBC. Functional PTEN inhibits ARE-dependent transcriptional activity, thus suppresses proteasome activity. BACH1 is involved in PTEN-mediated proteasome inhibition and regulated by PTEN-AKT1 axis.