Inhibition of 19S proteasome-associated deubiquitinases by metal-containing compounds

Liu, Ningning; Huang, Hongbiao; Dou, Q. Ping; Liu, Jinbao

doi:10.18632/oncoscience.167

Cited by 36 publications

(29 citation statements)

References 96 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As shown in Figure 2A, HA-UbVS strongly binds to both USP14 and UCHL5 in untreated cells, whereas the binding of HA-UbVS to USP14 and UCHL5 is weakened in the presence of NiPT in both A549 and H1299 cells, but to a less extent to the b-AP15-treated positive control cells. Previous reports showed that USP14 and UCHL5 are constitutively phosphorylated under normal conditions (31,32). Here, we observed that 5 µM NiPT caused the dephosphorylation of USP14 and UCHL5 at 12 h, which is similar to BTZ or b-AP15, two established proteasome deubiquitinase inhibitors (33, 34) ( Figure 2B).…”

Section: Nipt Inhibits Dubs Usp14 and Uchl5 And Promotes The Cytosolsupporting

confidence: 79%

“…We have been working on high-efficiency and low-toxicity metal complexes for many years. We used PT as the ligand, to synthetize a variety of metal complexes, such as CuPT, PtPT, and NiPT (24,25,31). Our previous studies have shown that they have good antitumor efficacy in vitro and in vivo via inhibiting the deubiquitinase activity of 26S proteasome.…”

Section: Discussionmentioning

confidence: 99%

“…Accumulative evidences have shown that deubiquitinase inhibitors suppress the growth of cancer cells in vitro and in vivo (6,25,28,31). Since the data above indicated that NiPT could induce autophagy, we next examined if suppressing autophagy will benefit the NiPT-induced cell death.…”

Section: Inhibition Of Autophagy Will Aggravate Apoptosis Of Lung Canmentioning

confidence: 99%

See 2 more Smart Citations

Autophagy Induced by Proteasomal DUB Inhibitor NiPT Restricts NiPT-Mediated Cancer Cell Death

Chen

et al. 2020

Front. Oncol.

Self Cite

View full text Add to dashboard Cite

Ubiquitin-proteasome system (UPS) and autophagy-lysosome pathway (ALP) are two major systems for protein quality control (PQC) in eukaryotic cells. Interconnectivity between these two pathways has been suggested, but the molecular detail of how they impact each other remains elusive. Proteasomal deubiquitinase (DUB) is an important constituent in the UPS and has proved to be a novel anticancer target. We have previously found that a novel DUB inhibitor, nickel complex NiPT, induces apoptosis in both cultured tumor cell lines and cancer cells from acute myeloid leukemia human patients. In this study, we found that NiPT triggered autophagy both in vitro and in vivo. Mechanistically, NiPT targets two DUBs, USP14, and UCHL5, and increased the total cellular level of polyubiquitination. Deletion of the Ubiquitin Associated (UBA) domain of P62 that is required for polyubiquitin binding prevented NiPT-induced autophagy. NiPTinduced autophagy is through either concomitant activation of AMP-activated protein kinase (AMPK) and inhibition of mechanistic target of rapamycin (mTOR) signaling, or eliciting endoplasmic reticulum (ER)-stress by activating activating transcription factor 4 (ATF4) and C/EBP-homologous protein (CHOP). Moreover, NiPT could induce more lung cancer cells undergoing apoptosis if it synergistically uses autophagy inhibitors, suggesting that NiPT-induced autophagy protects cancer cell from death. Collectively, our findings demonstrate that autophagy inhibition enhances the anticancer effects of proteasomal DUB inhibitor and might be an effective treatment strategy for lung cancer.

show abstract

Section: Nipt Inhibits Dubs Usp14 and Uchl5 And Promotes The Cytosolsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Autophagy Induced by Proteasomal DUB Inhibitor NiPT Restricts NiPT-Mediated Cancer Cell Death

Chen

et al. 2020

Front. Oncol.

Self Cite

View full text Add to dashboard Cite

show abstract

“…Several studies have suggested that the proteasome is an important cellular target of different environmental chemical families, such as, we have also shown that 20S proteasome is a molecular target of environmental toxic organotins . The results of the current study have shown that proteasomal DUBs, UCHL5 and USP14 are two novel targets for commonly used OBs.…”

Section: Discussionsupporting

confidence: 63%

Proteasome‐associated cysteine deubiquitinases are molecular targets of environmental optical brightener compounds

Castro

Ekinci

Huang

et al. 2019

J of Cellular Biochemistry

Self Cite

View full text Add to dashboard Cite

The levels of organic pollutants, such as optical brightener (OB) compounds, in the global environment have been increasing in recent years. The toxicological effects and signal transduction systems associated with OB toxicity have not been thoroughly studied. The ubiquitin-proteasome system (UPS) plays a crucial role in regulating multiple essential cellular processes, and proteasomeassociated cysteine deubiquitinases (DUBs), ubiquitin C-terminal hydrolase L5 (UCHL5) and USP14, are two major regulators for (de)ubiquitination and stability of many important target proteins. Therefore, potential inhibition of UCHL5 and USP14 activities by some environmental chemicals might cause in vivo toxicity. In the current study we hypothesize that electrophilic OB compounds, such as 4,4′-diamino-2,2′-stilbenedisulfonic acid (DAST), fluorescent brightener 28 (FB-28) and FB-71, can interact with the catalytic triads (CYS, HIS, and ASP) of UCHL5 and USP14 and inhibit their enzymatic activities, leading to cell growth suppression. This hypothesis is supported by our findings presented in this study. Results from in silico computational docking and ubiquitin vinyl sulfone assay confirmed the UCHL5/USP14inhibitory activities of these OB compounds that have potencies in an order of: FB-71 > FB-28 > DAST. Furthermore, inhibition of these two proteasomal DUBs by OBs resulted in cell growth inhibition and apoptosis induction in two human breast cancer cell models. In addition, we found that OB-mediated DUB inhibition triggers a feedback reaction in which expression of UCHL5 and USP14 proteins is increased to compromise the suppressed activities. Our study suggests that these commonly used OB compounds may target and inhibit proteasomal cysteine DUBs, which should contribute to their toxicological effects in vivo. K E Y W O R D S degradation, environmental pollutant, fluorescent brightening agent, molecular target, posttranslational modification

show abstract

“…Clinical drugs for treating other diseases previously, were found as DUB inhibitors. Pimozide (an anti-psychotic drug) was identified as inhibitors of USP1, and auranofin (a rheumatoid arthritis drug) is a proteasome-associated DUB inhibitor [154, 155]. Benefiting from high-throughput screening studies, LS1 as an UCHL3 inhibitor and PR-619 as a general DUB enzyme inhibitor [156, 157].…”

Section: Dubs Involved In Diseases and Dubs Targeting Therapeuticsmentioning

confidence: 99%

The emerging role of deubiquitinating enzymes in genomic integrity, diseases, and therapeutics

Zhou

Shah

et al. 2016

Cell Biosci

View full text Add to dashboard Cite

The addition of mono-ubiquitin or poly-ubiquitin chain to signaling proteins in response to DNA damage signal is thought to be a critical event that facilitates the recognition of DNA damage lesion site, the activation of checkpoint function, termination and checkpoint response and the recruitment of DNA repair proteins. Despite the ubiquitin modifiers, removal of ubiquitin from the functional proteins by the deubiquitinating enzymes (DUBs) plays an important role in orchestrating DNA damage response as well as DNA repair processes. Deregulated ubiquitination and deubiquitination could lead to genome instability that in turn causes tumorigenesis. Recent TCGA study has further revealed the connection between mutations in alteration of DUBs and various types of tumors. In addition, emerging drug design based on DUBs provides a new avenue for anti-cancer therapy. In this review, we will summarize the role of deubiquitination and specificity of DUBs, and highlight the recent discoveries of DUBs in the modulation of ubiquitin-mediated DNA damage response and DNA damage repair. We will furthermore discuss the DUBs involved in the tumorigenesis as well as interception of deubiquitination as a novel strategy for anti-cancer therapy.

show abstract

Inhibition of 19S proteasome-associated deubiquitinases by metal-containing compounds

Cited by 36 publications

References 96 publications

Autophagy Induced by Proteasomal DUB Inhibitor NiPT Restricts NiPT-Mediated Cancer Cell Death

Autophagy Induced by Proteasomal DUB Inhibitor NiPT Restricts NiPT-Mediated Cancer Cell Death

Proteasome‐associated cysteine deubiquitinases are molecular targets of environmental optical brightener compounds

The emerging role of deubiquitinating enzymes in genomic integrity, diseases, and therapeutics

Contact Info

Product

Resources

About