2018
DOI: 10.1159/000490210
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RA190, a Proteasome Subunit ADRM1 Inhibitor, Suppresses Intrahepatic Cholangiocarcinoma by Inducing NF-KB-Mediated Cell Apoptosis

Abstract: Background/Aims: Effective drug treatment for intrahepatic cholangiocarcinoma (ICC) is currently lacking. Therefore, there is an urgent need for new targets and new drugs that can prolong patient survival. Recently targeting the ubiquitin proteasome pathway has become an attractive anti-cancer strategy. In this study, we aimed to evaluate the therapeutic effect of and identify the potential mechanisms involved in targeting the proteasome subunit ADRM1 for ICC. Methods: The expression of ADRM1 and its prognosti… Show more

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Cited by 29 publications
(42 citation statements)
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“…Inhibition of IκBα degradation by proteasome inhibitors prevents the release and nuclear entry of NF-κB. RA190 was previously reported to block NF-κB signaling via stabilization of p-IκBα [11,12]. Here, we show that RA190 inhibits the NF-κB pathway by preventing IκBα degradation by the proteasome and causing the cytoplasmic accumulation of NF-κB.…”
Section: Introductionsupporting
confidence: 47%
See 1 more Smart Citation
“…Inhibition of IκBα degradation by proteasome inhibitors prevents the release and nuclear entry of NF-κB. RA190 was previously reported to block NF-κB signaling via stabilization of p-IκBα [11,12]. Here, we show that RA190 inhibits the NF-κB pathway by preventing IκBα degradation by the proteasome and causing the cytoplasmic accumulation of NF-κB.…”
Section: Introductionsupporting
confidence: 47%
“…The bis-benzylidine piperidone RA190 covalently binds to cysteine 88 of RPN13 (ADRM1), a key ubiquitin receptor in the 19S regulatory particle of the proteasome, and inhibits its function causing rapid accumulation of polyubiquitinated proteins. RA190 showed a therapeutic effect in multiple myeloma, cholangiocarconoma [11], ovarian and cervical cancer models in previous studies [12]. In this study, we examine the impact of RA190 on HCC, including the levels of polyubiquitinated proteins, Endoplasmic Reticulum Stress, apoptosis and its therapeutic potential.…”
Section: Introductionmentioning
confidence: 91%
“…The bis-benzylidine piperidone RA190 covalently binds to cysteine 88 of RPN13 (also called ADRM1), a key ubiquitin receptor in the 19S regulatory particle of the proteasome, and inhibits its function causing rapid accumulation of polyubiquitinated proteins. RA190 showed a therapeutic effect in multiple myeloma, cholangiocarcinoma [11], ovarian and cervical cancer models in previous studies [12]. In this study, we examine the impact of RA190 on HCC cells, including the levels of polyubiquitinated proteins, Endoplasmic Reticulum (ER) stress, apoptosis, and its therapeutic 5 potential against an orthotopic xenograft model.…”
Section: Introductionmentioning
confidence: 95%
“…Although binding to UCH37 can also occur in vitro [6], several lines of evidence including cell labeling [10], degrader [11] and knockout studies [12] suggest that RPN13 is RA190's principle cellular target. RA190 and the related RA183 [13] exhibit antineoplastic activity, including against bortezomib-resistant MM, and against solid tumors in pre-clinical models of ovarian cancer [10,13,14], human papillomavirus (HPV)-associated and several other solid cancers [6,12,[15][16][17][18]. Like RA190 and RA183 [13], the diphenyldihaloketones CLEFMA and EF-24 also adduct to RPN13 and inhibit proteasome function [19], and herein we seek to further understand the pharmacophore.…”
Section: Introductionmentioning
confidence: 99%