Blockade of deubiquitylating enzyme Rpn11 triggers apoptosis in multiple myeloma cells and overcomes bortezomib resistance

Song, Yan; S, Li; A, Ray; Ds, Das; Qi, Jianhua; Samur, Mehmet K.; Tai, Yu‐Tzu; Munshi, Nikhil C.; Rd, Carrasco; Chauhan, Dharminder; Kc, Anderson

doi:10.1038/onc.2017.172

Cited by 86 publications

(88 citation statements)

References 46 publications

(52 reference statements)

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“…Research on the efficacy of OPA as a potential cancer treatment has been started in MM. Studies indicate that OPA's metallopeptidase inhibition activity is linked to apoptosis in myeloma cell lines including cell lines, which were BTZ resistant [157].…”

Section: Ra190mentioning

confidence: 99%

Drug Development Targeting the Ubiquitin–Proteasome System (UPS) for the Treatment of Human Cancers

Zhang

Linder

Bazzaro

2020

Cancers

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Cancer cells are characterized by a higher rate of protein turnover and greater demand for protein homeostasis compared to normal cells. In this scenario, the ubiquitin-proteasome system (UPS), which is responsible for the degradation of over 80% of cellular proteins within mammalian cells, becomes vital to cancer cells, making the UPS a critical target for the discovery of novel cancer therapeutics. This review systematically categorizes all current reported small molecule inhibitors of the various essential components of the UPS, including ubiquitin-activating enzymes (E1s), ubiquitin-conjugating enzymes (E2s), ubiquitin ligases (E3s), the 20S proteasome catalytic core particle (20S CP) and the 19S proteasome regulatory particles (19S RP), as well as their mechanism/s of action and limitations. We also discuss the immunoproteasome which is considered as a prospective therapeutic target of the next generation of proteasome inhibitors in cancer therapies.Cancers 2020, 12, 902 2 of 34 core component of the nucleosome, which is critical for transcription and cell cycle, is recognized and linked by Lysine Residue 48 (K48) and further degraded by the proteasome [17,18]; DbpB (also named Y-box protein 1), a transcription factor, is reported to selectively recognize the Y-box promoter element. Studies showed that its terminal 105-amino-acid-long fragment is removed after a specific proteolytic cleavage by the proteasome complex [19,20]; NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) is located outside the nucleus and is reported to be involved in DNA transcription as well as cell survival [21,22]. The NF-κB p105 is the precursor of NF-κB p50. It is evident that NF-κB p105 is cleaved and selectively degraded at the C-terminus by proteasome, generating the active form of NF-κB p50 [23]. Products of UPS degradation can also be further degraded into single amino acids by aminopeptidases [24]. Aminopeptidases are the class of enzymes that catalyze the final steps in the ubiquitin-proteasome pathway by breaking down shorter peptides (<5 residues) into even smaller fragments [25]. Many, but not all, of aminopeptidases, are zinc metalloenzymes, such as leucine aminopeptidases (lAPs) and methionine aminopeptidases (metAPs) [26,27]. Studies showed that blocking the activity of the aminopeptidases by inhibitor of bestatin could generate a major accumulation of peptides which are ∼2-5 residues long [28].The 26S proteasome contains one/two 19S regulatory particles (19S RP) which mainly regulate the translocation of ubiquitinated proteins to the 20S CP and one 20S core particle (20S CP) in which proteolysis finally occurs [29,30]. In general, two main processes are associated with the process of degradation of proteins by the UPS: (1) tagging the to-be-degraded proteins by polyubiquitination (normally more than four ubiquitins), and (2) proteolytic degradation of the polyubiquitinated protein by the 26S proteasome complex [31,32]. Each step incorporates an intricate and complex spectrum of protein interaction...

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Section: Ra190mentioning

confidence: 99%

Drug Development Targeting the Ubiquitin–Proteasome System (UPS) for the Treatment of Human Cancers

Zhang

Linder

Bazzaro

2020

Cancers

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“…We and others previously showed that chemical inhibition of Rpn11 blocks cancer cell proliferation (Li et al, 2017; Song et al, 2017). We measured the effects of ETPs on the proliferation of HCT116 human colon cancer cells and calculated inhibition of cell growth (GI 50 ) (Table S2).…”

Section: Resultsmentioning

confidence: 98%

Epidithiodiketopiperazines Inhibit Protein Degradation by Targeting Proteasome Deubiquitinase Rpn11

Zhang

Santos

et al. 2018

Cell Chemical Biology

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The 26S proteasome is the major proteolytic machine for breaking down cytosolic and nuclear proteins in eukaryotes. Due to the lack of a suitable assay, it is difficult to measure routinely and quantitatively the breakdown of proteins by the 26S proteasome in vitro. In the present study, we developed an assay to monitor proteasome-mediated protein degradation. Using this assay, we discovered that epidithiodiketopiperazine (ETPs) blocked the degradation of our model substrate in vitro. Further characterization revealed that ETPs inhibited proteasome function by targeting the essential proteasomal deubiquitinase Rpn11 (POH1/PSMD14). ETPs also inhibited other JAMM (JAB1/MPN/Mov34 metalloenzyme) proteases such as Csn5 and AMSH. An improved ETP with fewer non-specific effects, SOP11, stabilized a subset of proteasome substrates in cells, induced the unfolded protein response, and led to cell death. SOP11 represents a class of Rpn11 inhibitor and provides an alternative route to develop proteasome inhibitors.

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“…Moreover, because CZM was discovered as a new drug for cancer treatment 37 , it would be now interesting to investigate whether part of its anti-cancer effects could be the result of inhibiting Golgi-to-ER retrograde pathway. Interestingly, recent studies have shown that PSMD14 is upregulated (mRNA and protein levels) in different tumoral cell types 81, 82 . Whether cancer cells are more dependent of Golgi-to-ER retrograde pathway than normal cells, as it happens regarding the mechanisms of protein quality control 83 is still unclear.…”

Section: Discussionmentioning

confidence: 99%

The proteasomal deubiquitinating enzyme PSMD14 regulates macroautophagy by controlling Golgi-to-ER retrograde transport

Bustamante

Cereceda

González

et al. 2020

Preprint

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31Ubiquitination regulates several biological processes. Here, we search for ubiquitin-related 32 genes implicated in protein membrane trafficking performing a High-Content siRNA 33 Screening including 1,187 genes of the human "ubiquitinome" using Amyloid Precursor 34 Protein (APP) as a reporter. We identified the deubiquitinating enzyme PSMD14, a subunit 35 of the 19S regulatory particle of the proteasome, specific for K63-Ub chains in cells, as a 36novel key regulator of Golgi-to-endoplasmic reticulum (ER) retrograde transport. Silencing 37 or pharmacological inhibition of PSMD14 caused a robust and rapid inhibition of Golgi-to-38 ER retrograde transport which leads to a potent blockage of macroautophagy by a 39 mechanism associated with the retention of Atg9A and Rab1A at the Golgi apparatus. 40Because pharmacological inhibition of the proteolytic core of the 20S proteasome did not 41 recapitulate these effects, we concluded that PSMD14, and their K-63-Ub chains, act as a 42 crucial regulator factor for macroautophagy by controlling Golgi-to-ER retrograde 43 transport. 44

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Blockade of deubiquitylating enzyme Rpn11 triggers apoptosis in multiple myeloma cells and overcomes bortezomib resistance

Cited by 86 publications

References 46 publications

Drug Development Targeting the Ubiquitin–Proteasome System (UPS) for the Treatment of Human Cancers

Drug Development Targeting the Ubiquitin–Proteasome System (UPS) for the Treatment of Human Cancers

Epidithiodiketopiperazines Inhibit Protein Degradation by Targeting Proteasome Deubiquitinase Rpn11

The proteasomal deubiquitinating enzyme PSMD14 regulates macroautophagy by controlling Golgi-to-ER retrograde transport

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