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- Title
PTEN status determines chemosensitivity to proteasome inhibition in cholangiocarcinoma.
- Authors
Jiang, Tian-Yi; Pan, Yu-Fei; Wan, Zheng-Hua; Lin, Yun-Kai; Zhu, Bin; Yuan, Zhen-gang; Ma, Yun-Han; Shi, Yuan-Yuan; Zeng, Tian-Mei; Dong, Li-Wei; Tan, Ye-Xiong; Wang, Hong-Yang
- Abstract
A chink in cholangiocarcinoma's armor: Cholangiocarcinoma is a bile duct cancer with limited therapeutic options and no established second-line treatment. In a screening assay looking for potential therapies to treat cholangiocarcinoma, Jiang et al. identified proteasome inhibitors, an established category of anticancer drugs. The authors also observed that a deficiency of the tumor suppressor PTEN, seen in many cancers including cholangiocarcinoma, sensitized the tumors to proteasome inhibitors. The researchers identified the mechanism underlying this interaction between PTEN and proteasome activity and assessed the therapeutic potential of proteasome inhibitors in mouse models as well as two patients with cholangiocarcinoma. Patient-derived xenografts (PDXs) and PDX-derived cells (PDCs) are useful in preclinical research. We performed a drug screening assay using PDCs and identified proteasome inhibitors as promising drugs for cholangiocarcinoma (CCA) treatment. Furthermore, we determined that phosphate and tensin homology deleted on chromosome ten (PTEN) deficiency promotes protein synthesis and proteasome subunit expression and proteolytic activity, creating a dependency on the proteasome for cancer cell growth and survival. Thus, targeting the proteasome machinery with the inhibitor bortezomib inhibited the proliferation and survival of CCA cells lacking functional PTEN. Therapeutic evaluation of PDXs, autochthonous mouse models, and patients confirmed this dependency on the proteasome. Mechanistically, we found that PTEN promoted the nuclear translocation of FOXO1, resulting in the increased expression of BACH1 and MAFF. BACH1 and MAFF are transcriptional regulators that recognize the antioxidant response element, which is present in genes encoding proteasome subunits. PTEN induced the accumulation and nuclear translocation of these proteins, which directly repressed the transcription of genes encoding proteasome subunits. We revealed that the PTEN-proteasome axis is a potential target for therapy in PTEN-deficient CCA and other PTEN-deficient cancers.
- Subjects
BILIARY tract cancer; CHOLANGIOCARCINOMA; PROTEASOME inhibitors; CANCER cell growth; INTRAHEPATIC bile ducts
- Publication
Science Translational Medicine, 2020, Vol 12, Issue 562, p1
- ISSN
1946-6234
- Publication type
Article
- DOI
10.1126/scitranslmed.aay0152