PTEN status determines chemosensitivity to proteasome inhibition in cholangiocarcinoma.

Abstract:

: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.

journal_name

Sci Transl Med

authors

Jiang TY,Pan YF,Wan ZH,Lin YK,Zhu B,Yuan ZG,Ma YH,Shi YY,Zeng TM,Dong LW,Tan YX,Wang HY

doi

10.1126/scitranslmed.aay0152

subject

Has Abstract

pub_date

2020-09-23 00:00:00

issue

562

eissn

1946-6234

issn

1946-6242

pii

12/562/eaay0152

journal_volume

12

pub_type

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