Targeting Deubiquitinating Enzymes and Autophagy in Cancer

Mooneyham, Ashley; Bazzaro, Martina

doi:10.1007/978-1-4939-6539-7_5

Cited by 10 publications

(7 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Another study has shown that the UPS pathway plays an indispensable role in the regulation of mitochondrial energy metabolism by regulating the turnover of several mitochondrial oxidative phosphorylation (OXPHOS) proteins such as the succinate dehydrogenase subunit A (SDHA), the mitochondrial respiratory complex II [63,64]. Findings also indicate a mechanism of crosstalk between the proteasome and autophagy pathway [65][66][67][68][69]. This includes the degradation of synaptosomal-associated protein 29 (SNAP29) and syntaxin 17 (STX17) by the ubiquitin-independent 20S proteasome [70].…”

Section: The Ups and Tumor Metabolismmentioning

confidence: 99%

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

Zhang

Linder

Bazzaro

2020

Cancers

Self Cite

View full text Add to dashboard Cite

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...

show abstract

Section: The Ups and Tumor Metabolismmentioning

confidence: 99%

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

Zhang

Linder

Bazzaro

2020

Cancers

Self Cite

View full text Add to dashboard Cite

show abstract

“…TrxR inhibition therefore cannot be the main effector of the oxidative and proteotoxic stress observed with these compounds.Another potential target of these reactive compounds that could result in similar proteotoxic effects is the proteasomal ubiquitin receptor Rpn13. The small molecule inhibitor which selectively targets Rpn13 to inhibit proteasomal degradation closely resembles b-AP15 and VLX1570[342]. This raises the possibility that the observed proteotoxic effects in Paper IV are due to inhibition of ubiquitin binding to the proteasome.…”

mentioning

confidence: 97%

Proteasome inhibitor b-AP15 induces enhanced proteotoxicity by inhibiting cytoprotective aggresome formation

et al. 2019

View full text Add to dashboard Cite

“…In tumors, autophagy is believed to promote tumor growth and progression by helping cells adapt to the harsh tumor microenvironment. Therefore, some autophagy inhibitors, such as hydroxychloroquine (HCQ), are used in anti-cancer treatment strategies [16]. Recent studies have found that IU1 could induce autophagy in cancer cells [15].…”

Section: Discussionmentioning

confidence: 99%

“…We propose that IU1 regulates MDM2 protein levels by a post-translational mechanism. The proteasome system UPS and the autophagy system, are the two primary pathways in intracellular protein degradation 16 - 18 . Here, we showed that IU1 treatment promoted UPS function and activated autophagy.…”

Section: Introductionmentioning

confidence: 99%

IU1 suppresses proliferation of cervical cancer cells through MDM2 degradation

et al. 2020

View full text Add to dashboard Cite

Previous studies have demonstrated that the antitumor potential of IU1 (a pharmacological compound), which was mediated by selective inhibition of proteasome-associated deubiquitinase ubiquitin-specific protease 14 (USP14). However, the underlying molecular mechanisms remain elusive. It has been well established that mdm2 (Murine double minute 2) gene was amplified and/or overexpressed in a variety of human neoplasms, including cervical cancer. Furthermore, MDM2 is critical to cervical cancer development and progression. Relatively studies have reported that USP15 and USP7 stabilized MDM2 protein levels by removing its ubiquitin chain. In the current study, we studied the cell proliferation status after IU1 treatment and the USP14-MDM2 protein interaction in cervical cancer cells. This study experimentally revealed that IU1 treatment reduced MDM2 protein expression in HeLa cervical cancer cells, along with the activation of autophagy-lysosomal protein degradation and promotion of ubiquitin-proteasome system (UPS) function, thereby blocked G0/G1 to S phase transition, decreased cell growth and triggered cell apoptosis. Thus, these results indicate that IU1 treatment simultaneously targets two major intracellular protein degradation systems, ubiquitin-proteasome and autophagy-lysosome systems, which leads to MDM2 degradation and contributes to the antitumor effect of IU1.

show abstract

Targeting Deubiquitinating Enzymes and Autophagy in Cancer

Cited by 10 publications

References 45 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

Proteasome inhibitor b-AP15 induces enhanced proteotoxicity by inhibiting cytoprotective aggresome formation

IU1 suppresses proliferation of cervical cancer cells through MDM2 degradation

Contact Info

Product

Resources

About