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RA190, a Proteasome Subunit ADRM1 Inhibitor, Suppresses Intrahepatic Cholangiocarcinoma by Inducing NF-KB-Mediated
Guang-Yang Yu1, Xuan Wang1, Su-Su Zheng2
1Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute & Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
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 prognostic value in ICC was analyzed using GEO and TCGA datasets, tumor tissues, and tumor tissue arrays. The effects of RA190 on the proliferation and survival of both established ICC cell lines and primary ICC cells were examined in vitro. Annexin V/propidium iodide staining, western blotting and immunohistochemical staining were performed. The in vivo anti-tumor effect of RA190 on ICC was validated in subcutaneous xenograft and patient-derived xenograft (PDX) models.
Results:
ADRM1 levels were significantly higher in ICC tissues than in normal bile duct tissues. ICC patients with high ADRM1 levels had worse overall survival (hazard ratio [HR] = 2.383, 95% confidence interval [CI] =1.357 to 4.188) and recurrence-free survival (HR = 1.710, 95% CI =1.045 to 2.796). ADRM1 knockdown significantly inhibited ICC growth in vitro and in vivo. The specific inhibitor RA190 targeting ADRM1 suppressed proliferation and reduced cell vitality of ICC cell lines and primary ICC cells significantly in vitro. Furthermore, RA190 significantly inhibited the proteasome by inactivating ADRM1, and the consequent accumulation of ADRM1 substrates decreased the activating levels of NF-κB to aggravate cell apoptosis. The therapeutic benefits of RA190 treatment were further demonstrated in both subcutaneous implantation and PDX models.
Conclusions:
Our findings indicate that up-regulated ADRM1 was involved in ICC progression and suggest the potential clinical application of ADRM1 inhibitors (e.g., RA190 and KDT-11) for ICC treatment.
Insights
Targeting ADRM1, a proteasome subunit, shows promise for intrahepatic cholangiocarcinoma (ICC) treatment. The inhibitor RA190 effectively suppressed ICC growth in preclinical models, suggesting a new therapeutic strategy for this challenging cancer.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Intrahepatic cholangiocarcinoma (ICC) lacks effective drug treatments, necessitating novel therapeutic targets.
- Targeting the ubiquitin-proteasome pathway presents a promising anti-cancer strategy.
- The proteasome subunit ADRM1 is a potential therapeutic target for ICC.
Purpose of the Study:
- To evaluate the therapeutic effect of targeting ADRM1 in ICC.
- To identify the mechanisms underlying ADRM1 inhibition in ICC.
- To assess the efficacy of the ADRM1 inhibitor RA190 in ICC models.
Main Methods:
- Analyzed ADRM1 expression and prognostic value in ICC using public datasets (GEO, TCGA) and patient tissues.
- Investigated the in vitro effects of RA190 on ICC cell proliferation and survival.
- Validated the in vivo anti-tumor efficacy of RA190 in xenograft and patient-derived xenograft (PDX) models.
Main Results:
- ADRM1 was significantly upregulated in ICC tissues and associated with poorer patient survival.
- ADRM1 knockdown inhibited ICC growth in vitro and in vivo.
- RA190 suppressed ICC cell proliferation, induced apoptosis via NF-κB inhibition, and demonstrated significant anti-tumor effects in vivo.
Conclusions:
- Upregulated ADRM1 is implicated in ICC progression.
- ADRM1 inhibitors, such as RA190, hold potential for clinical application in ICC treatment.
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