PTEN status determines chemosensitivity to proteasome inhibition in 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 homol...

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Published in:Science translational medicine 2020-09, Vol.12 (562)
Main 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
Format: Article
Language:English
Subjects:
Animal models
Animals
Antioxidants
Bile Duct Neoplasms - drug therapy
Bile Ducts, Intrahepatic
Bortezomib
Bortezomib - pharmacology
Bortezomib - therapeutic use
Cell Line, Tumor
Cell proliferation
Cell survival
Cholangiocarcinoma
Cholangiocarcinoma - drug therapy
Drug screening
FOXO1 protein
Homology
Humans
Mice
Nuclear transport
Proteasome Endopeptidase Complex
Proteasome inhibitors
Protein biosynthesis
Protein deficiency
Proteolysis
PTEN Phosphohydrolase - genetics
PTEN protein
Tensin
Transcription
Xenografts
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Summary: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 and 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.
ISSN:1946-6234
1946-6242
1946-3242
DOI:10.1126/scitranslmed.aay0152