Upregulation of NPL4 promotes bladder cancer cell proliferation by inhibiting DXO destabilization of cyclin D1 mRNA

Lu, Bao‐Sai; Yin, Yuewei; Zhang, Yanping; Guo, Ping-Ying; Li, Wei; Liu, Kailong

doi:10.1186/s12935-019-0874-2

Cited by 10 publications

(12 citation statements)

References 47 publications

(50 reference statements)

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“…In this paper, NPL4 aggregation with its increased intensity was also indicated in 786-o cells after disulfiram treatment. Moreover, Lu et al showed that NPL4 was upregulated in bladder cancer tissue and was correlated with poor prognosis; NPL4 knockdown was found to decrease bladder cancer cell proliferation by reduction of cyclin D1 expression [ 27 ]. Because NPL4 is the most important cofactor of p97, NPL4, which can be targeted by disulfiram, is also a key molecule for the treatment of cancers.…”

Section: Discussionmentioning

confidence: 99%

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Targeting NPL4 via drug repositioning using disulfiram for the treatment of clear cell renal cell carcinoma

et al. 2020

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The alcohol-abuse drug disulfiram has antitumor effects against diverse cancer types via inhibition of the ubiquitin-proteasome protein nuclear protein localization protein 4 (NPL4). However, the antitumor effects of NPL4 and disulfiram in clear cell renal cell carcinoma (ccRCC) are unclear. Here, we evaluated the therapeutic potential of targeting the ubiquitinproteasome pathway using disulfiram and RNA interference and investigated the mechanisms underlying disulfiram in ccRCC. According to data from The Cancer Genome Atlas, NPL4 mRNA expression was significantly upregulated in clinical ccRCC samples compared with that in normal kidney samples, and patients with high NPL4 expression had poor overall survival compared with patients with low NPL4 expression. Disulfiram and NPL4 siRNA inhibited ccRCC cell proliferation in vitro, and disulfiram inhibited ccRCC tumor growth in a xenograft model. Synergistic antiproliferative effects were observed for combination treatment with disulfiram and sunitinib in vitro and in vivo. In RCC cells from mice treated with disulfiram and/or sunitinib, several genes associated with serine biosynthesis and aldose reductase were downregulated in cells treated with disulfiram or sunitinib alone and further downregulated in cells treated with both disulfiram and sunitinib. These findings provided insights into the mechanisms of disulfiram and suggested novel therapeutic strategies for RCC treatment.

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Section: Discussionmentioning

confidence: 99%

“…upregulated in bladder cancer tissue and was correlated with poor prognosis; NPL4 knockdown was found to decrease bladder cancer cell proliferation by reduction of cyclin D1 expression [27]. Because NPL4 is the most important cofactor of p97, NPL4, which can be targeted by disulfiram, is also a key molecule for the treatment of cancers.…”

Section: Plos Onementioning

confidence: 99%

Targeting NPL4 via drug repositioning using disulfiram for the treatment of clear cell renal cell carcinoma

et al. 2020

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“…Hyperosmotic stress induces phase separation of proteasome-containing nuclear foci (containing ubiquitinated proteins, VCP, and several proteasome-related proteins), which collectively constitute a proteolytic site ( Yasuda et al, 2020 ). Compared to normal cells, cancer cells are characterized with upregulation of the VCP-UFD1-NPLOC4 pathway to digest false-synthesized and misfolded proteins ( Tsujimoto et al, 2004 ; Yamamoto et al, 2004 ; Huiting et al, 2018 ; Lu et al, 2019 ). Thus, inhibition of the VCP-UFD1-NPLOC4 pathway may represent as a selective treatment option for cancer.…”

Section: Er-associated Degradation: a Quality-controlled Degradation Of Misfolded Proteinsmentioning

confidence: 99%

Targeting Ubiquitin–Proteasome System With Copper Complexes for Cancer Therapy

Chen

Dou

Liu

et al. 2021

Front. Mol. Biosci.

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Characterizing mechanisms of protein homeostasis, a process of balancing between protein synthesis and protein degradation, is important for understanding the potential causes of human diseases. The ubiquitin–proteasome system (UPS) is a well-studied mechanism of protein catabolism, which is responsible for eliminating misfolded, damaged, or aging proteins, thereby maintaining quality and quantity of cellular proteins. The UPS is composed of multiple components, including a series of enzymes (E1, E2, E3, and deubiquitinase [DUB]) and 26S proteasome (19S regulatory particles + 20S core particle). An impaired UPS pathway is involved in multiple diseases, including cancer. Several proteasome inhibitors, such as bortezomib, carfilzomib, and ixazomib, are approved to treat patients with certain cancers. However, their applications are limited by side effects, drug resistance, and drug–drug interactions observed in their clinical processes. To overcome these shortcomings, alternative UPS inhibitors have been searched for in many fields. Copper complexes (e.g., CuET, CuHQ, CuCQ, CuPDTC, CuPT, and CuHK) are found to be able to inhibit a core component of the UPS machinery, such as 20S proteasome, 19S DUBs, and NPLOC4/NPL4 complex, and are proposed to be one class of metal-based anticancer drugs. In this review, we will summarize functions and applications of copper complexes in a concise perspective, with a focus on connections between the UPS and cancer.

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“…It has been revealed that cell proliferation was increased by DXO downregulation and destabilizing cyclin D1 mRNA in bladder cancer. However, genes controlled by this transcription factor have not yet been identified, indicating that more research is required to be performed [60].…”

Section: Discussionmentioning

confidence: 99%

Evaluation of the Effectiveness of Herbal Components Based on Their Regulatory Signature on Carcinogenic Cancer Cells

Esmaeili

Lohrasebi

Mohammadi‐Dehcheshmeh

et al. 2021

Cells

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Predicting cancer cells’ response to a plant-derived agent is critical for the drug discovery process. Recently transcriptomes advancements have provided an opportunity to identify regulatory signatures to predict drug activity. Here in this study, a combination of meta-analysis and machine learning models have been used to determine regulatory signatures focusing on differentially expressed transcription factors (TFs) of herbal components on cancer cells. In order to increase the size of the dataset, six datasets were combined in a meta-analysis from studies that had evaluated the gene expression in cancer cell lines before and after herbal extract treatments. Then, categorical feature analysis based on the machine learning methods was applied to examine transcription factors in order to find the best signature/pattern capable of discriminating between control and treated groups. It was found that this integrative approach could recognize the combination of TFs as predictive biomarkers. It was observed that the random forest (RF) model produced the best combination rules, including AIP/TFE3/VGLL4/ID1 and AIP/ZNF7/DXO with the highest modulating capacity. As the RF algorithm combines the output of many trees to set up an ultimate model, its predictive rules are more accurate and reproducible than other trees. The discovered regulatory signature suggests an effective procedure to figure out the efficacy of investigational herbal compounds on particular cells in the drug discovery process.

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Upregulation of NPL4 promotes bladder cancer cell proliferation by inhibiting DXO destabilization of cyclin D1 mRNA

Cited by 10 publications

References 47 publications

Targeting NPL4 via drug repositioning using disulfiram for the treatment of clear cell renal cell carcinoma

Targeting NPL4 via drug repositioning using disulfiram for the treatment of clear cell renal cell carcinoma

Targeting Ubiquitin–Proteasome System With Copper Complexes for Cancer Therapy

Evaluation of the Effectiveness of Herbal Components Based on Their Regulatory Signature on Carcinogenic Cancer Cells

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