Dysregulation of the Ubiquitin Proteasome System in Human Malignancies: A Window for Therapeutic Intervention

Fhu, Chee Wai; Ali, Azhar

doi:10.3390/cancers13071513

Cited by 34 publications

(31 citation statements)

References 215 publications

(125 reference statements)

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“…We hypothesized that conditions of stress, which are often associated with the fast-growing tumor are involved in Hpa2 gene regulation. To examine this possibility, we focused on the proteasome that is often dysregulated in human malignancies [41] . We exposed gastric carcinoma cell lines to MG132, an inhibitor of the proteasome, resulting in massive accumulation of proteins tagged for degradation, leading to severe proteotoxic stress [42] .…”

Section: Resultsmentioning

confidence: 99%

Role of heparanase 2 (Hpa2) in gastric cancer

Liu¹,

Knani²,

Gross-Cohen³

et al. 2021

Neoplasia

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Highlight We report that gastric cancer patients exhibiting high levels of heparanase 2 (Hpa2) survive longer. Similarly, mice administrated with gastric carcinoma cells engineered to overexpress Hpa2 produced smaller tumors and survived longer than mice administrated with control cells. These beneficial effects were found to associate with increased phosphorylation of AMP-activated protein kinase (AMPK) that play an instrumental role in cell metabolism and is situated at the center of a tumor suppressor network. We also found that MG132, an inhibitor of the proteasome that results in proteotoxic stress, prominently enhances Hpa2 expression. Notably, Hpa2 induction by MG132 appeared to be mediated by AMPK, thus establishing a loop that feeds itself where Hpa2 enhances AMPK phosphorylation that, in turn, induces Hpa2 expression, possibly leading to attenuation of gastric tumorigenesis.

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Section: Resultsmentioning

confidence: 99%

Role of heparanase 2 (Hpa2) in gastric cancer

Liu¹,

Knani²,

Gross-Cohen³

et al. 2021

Neoplasia

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“…A majority of intracellular proteins are modified by ubiquitination ( Amm et al, 2014 ). Several Ub signals are recognized by proteasomes, thereby serving as a regulatory mechanism for protein degradation, affecting nearly all aspects of cellular processes ( Chowdhury and Enenkel, 2015 ; Hanna et al, 2019 ; Sakai et al, 2020 ; Fhu and Ali, 2021 ; Goetzke et al, 2021 ; Qu et al, 2021 ; Zou and Lin, 2021 ). Ubiquitin signaling is strictly regulated by a multistep cascade reaction consisting of three enzyme groups.…”

Section: Introductionmentioning

confidence: 99%

Functions and Molecular Mechanisms of Deltex Family Ubiquitin E3 Ligases in Development and Disease

Wang

Sun

et al. 2021

Front. Cell Dev. Biol.

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Ubiquitination is a posttranslational modification of proteins that significantly affects protein stability and function. The specificity of substrate recognition is determined by ubiquitin E3 ligase during ubiquitination. Human Deltex (DTX) protein family, which functions as ubiquitin E3 ligases, comprises five members, namely, DTX1, DTX2, DTX3, DTX3L, and DTX4. The characteristics and functional diversity of the DTX family proteins have attracted significant attention over the last decade. DTX proteins have several physiological and pathological roles and are closely associated with cell signal transduction, growth, differentiation, and apoptosis, as well as the occurrence and development of various tumors. Although they have been extensively studied in various species, data on structural features, biological functions, and potential mechanisms of action of the DTX family proteins remain limited. In this review, recent research progress on each member of the DTX family is summarized, providing insights into future research directions and potential strategies in disease diagnosis and therapy.

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“…The UPS (ubiquitin-proteasome system) removes small damaged proteins and protein aggregates and protects tissues from oxidative damage [50]. The UPS is responsible for the selective degradation of proteins engaged in cellular metabolism, for example, in regulating the cell cycle, apoptosis, and gene expression [21,51]. Higher expression of proteasome and its activity in malignant cells increase the degradation of cycle-controlling proteins and apoptosis, which leads to neoplasm growth.…”

Section: Discussionmentioning

confidence: 99%

“…The relationship between the ubiquitin-proteasome system and cancer progression has become a topic of increasing interest. The ubiquitin-proteasome system (UPS) is involved in intracellular protein degradation and the regulation of many cellular processes such as the cell cycle, induction of immune response, and gene expression [20][21][22]. These processes are highly relevant to tumour progression and carcinogenesis [23].…”

Section: Introductionmentioning

confidence: 99%

Application of SPRi Biosensors for Determination of 20S Proteasome and UCH-L1 Levels in the Serum and Urine of Transitional Bladder Cancer Patients

2021

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The ubiquitin–proteasome system (UPS) participates in the degradation of proteins which play an important role in regulating the cell cycle, apoptosis, and angiogenesis, as well as in the immune system. These processes are important in carcinogenesis. Transitional cell carcinoma (TCC) is one of the predominant types of bladder cancer. The relationship between the ubiquitin–proteasome system and cancer progression has become a topic of increasing interest among researchers. In this work, we propose an application of surface plasmon resonance imaging (SPRi)-based biosensors for the detection of 20S proteasome and ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) in the blood serum and urine of patients with TCC. The aim of the study was to determine 20S proteasome and UCH-L1 concentrations and to correlate the results with clinicopathological parameters. The group of subjects consisted of 82 patients with confirmed TCC, in addition to a control group of 27 healthy volunteers. It was found that 20S proteasome and UCH-L1 concentrations were significantly elevated in both the serum and urine of TCC patients, compared with the healthy subjects. There was a correlation between 20S proteasome concentrations in serum and urine, as well as between serum proteasome and UCH-L1 concentration. The SPRi biosensor sensitive to 20S proteasome using PSI inhibitor as the receptor, and the SPRi biosensor sensitive to the UCH-L1 protein using the protein-specific antibody as the receptor is suitable for the determination of 20S proteasome and UCH-L1 in body fluids and can serve as useful tools in the investigation of cancer biomarkers.

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Dysregulation of the Ubiquitin Proteasome System in Human Malignancies: A Window for Therapeutic Intervention

Cited by 34 publications

References 215 publications

Role of heparanase 2 (Hpa2) in gastric cancer

Role of heparanase 2 (Hpa2) in gastric cancer

Functions and Molecular Mechanisms of Deltex Family Ubiquitin E3 Ligases in Development and Disease

Application of SPRi Biosensors for Determination of 20S Proteasome and UCH-L1 Levels in the Serum and Urine of Transitional Bladder Cancer Patients

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