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.

The transcription factor BACH1 at the crossroads of cancer biology: From epithelial–mesenchymal transition to ferroptosis

“…( 80 ) Cholangiocarcinoma PMSA5 a Proteasome Repression ChIP, RT-PCR Jiang et al. ( 144 ) Colorectal melanoma CDKN2A b Cell cycle Repression ChIP, RT-PCR Fang et al. ( 126 , 127 ) Abbreviation: ChIP, chromatin immunoprecipitation.…”

Patient-Derived Xenograft Models for Intrahepatic Cholangiocarcinoma and Their Application in Guiding Personalized Medicine

“…Therefore, PDX model provides an alternative preclinical model for the discovery of novel treatment regimens for patients with malignant tumors. Recently, Wang et al constructed a cholangiocarcinoma PDX biobank with an engraftment rate of 83.3% (30 of 36) and used these models to reveal the chemosensitivity of proteasome inhibition in cholangiocarcinoma, which further broadened the application in medical research (17). The first report on ICC PDX model was published in 2016 by Giuliana et al, who successfully established and confirmed the histological and genetic similarity between primary tumor and PDX model (18).…”

PNO1 promotes human cholangiocarcinoma tumorigenesis and chemosensitivity

“…Meanwhile, one rejoices in surprise realizing that PNO1 de cient caused a signi cant increase in protein levels of PTEN and p53 in vivo. A previous study reported that PTEN inhibited proteasome activity and attenuated bortezomib e cacy in CHOL [39]. PTEN might modulate the function of proteasomes [40].…”

“…In addition, co-IP analysis indicated that PNO1 knockdown increased the binding of p53 to PTEN ( Figure 6B). It has been reported that PTEN attenuated bortezomib e cacy in CHOL treatment [17]. To explore the effect of manipulating PNO1 abundance on sensitivity to bortezomib, cell models in vitro and PDXs models in vivo were established.…”