Inhibition of USP14 induces ER stress–mediated autophagy without apoptosis in lung cancer cell line A549

Moghadami, Aliasghar; Beilankouhi, Elmira Aboutalebi Vand; Kalantary‐Charvadeh, Ashkan; Hamzavi, Masoud; Mosayyebi, Bashir; Sedghi, H.; Haghjo, Amir Ghorbani; Ahmad, Saeed Nazari Soltan

doi:10.1007/s12192-020-01125-w

Cited by 15 publications

(14 citation statements)

References 34 publications

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“…Increasing literature indicated the correlation between USP family and autophagy. The deletion of USP14 can activate endoplasmic reticulum stress-mediated autophagy [ 24 ]. USP13 knockdown increases p-tau ubiquitination via the 20S proteasome and p-tau clearance via autophagy [ 25 ].…”

Section: Discussionmentioning

confidence: 99%

The Protective Effect of Cyanidin‐3‐Glucoside on Myocardial Ischemia‐Reperfusion Injury through Ferroptosis

Shan

Yin

et al. 2021

Oxidative Medicine and Cellular Longevity

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This study was conducted to estimate the protective effect of Cyanidin-3-glucoside (C3G) on myocardial ischemia-reperfusion (IR) injury and to explore its mechanism. The rats were subjected to left anterior descending ligation and perfusion surgery. In vitro experiments were performed on H9c2 cells using the oxygen-glucose deprivation/reoxygenation (OGD/R) model. The results showed the administration of C3G reduced the infarction area, mitigated pathological alterations, inhibited ST segment elevation, and attenuated oxidative stress and ferroptosis-related protein expression. C3G also suppressed the expressions of USP19, Beclin1, NCOA4, and LC3II/LC3I. In addition, treatment with C3G relieved oxidative stress, downregulated LC3II/LC3I, reduced autophagosome number, downregulated TfR1 expression, and upregulated the expressions of FTH1 and GPX4 in OGD/R-induced H9c2 cells. C3G could inhibit the protein levels of USP19 and LC3II. C3G promoted K11-linked ubiquitination of Beclin1. Further evidence that C3G reduced ferroptosis and ameliorated myocardial I/R injury was demonstrated with the ferroptosis promoter RSL3. Taken together, C3G could be a potential agent to protect myocardium from myocardial I/R injury.

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Section: Discussionmentioning

confidence: 99%

The Protective Effect of Cyanidin‐3‐Glucoside on Myocardial Ischemia‐Reperfusion Injury through Ferroptosis

Shan

Yin

et al. 2021

Oxidative Medicine and Cellular Longevity

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“…In vitro and in vivo studies have shown that genetic and pharmacological inhibition of USP14 induces degradation of an androgen receptor (AR), favoring tumor suppression in AR-positive breast cancer cells or prostate cancer cells ( Liao et al, 2017 ; Liao et al, 2018 ). USP14 promotes tumor growth by regulating DNA damage response or ER stress-mediated autophagy in non-small cell lung cancer cells ( Moghadami et al, 2020 ; Sharma and Almasan, 2020 ). Alone this line, several compounds targeting UCHL5 and USP14 have been developed, including b-AP15 ( D'Arcy et al, 2011 ), VLX1570 (b-AP15 analog) ( Wang et al, 2016 ), AC17 (curcumin analog) ( Zhou et al, 2013 ), and various metal-based complexes ( Liu et al, 2014b ; Chen et al, 2018a ; Li et al, 2019a ).…”

Section: Targeting Dubs: a Novel Strategy For Cancer Therapymentioning

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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“…Furthermore, inhibition of USP14 led to the accumulation of ubiquitinated proteins, overwhelming the capacity of the ER and triggering ER-mediated autophagy. In A549 lung cancer cells, inhibition of USP14 induced ER stress-mediated autophagy by activating JNK1 ( Table 2 ) ( Moghadami et al, 2020 ). These findings indicated a new mechanism by which inhibition of USP14 causes ER stress-mediated autophagy in A549 lung cancer cells ( Figure 5 ).…”

Section: Biological Functions Of Usp14mentioning

confidence: 99%

USP14: Structure, Function, and Target Inhibition

Wang

Ning

et al. 2022

Front. Pharmacol.

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Ubiquitin-specific protease 14 (USP14), a deubiquitinating enzyme (DUB), is associated with proteasomes and exerts a dual function in regulating protein degradation. USP14 protects protein substrates from degradation by removing ubiquitin chains from proteasome-bound substrates, whereas promotes protein degradation by activating the proteasome. Increasing evidence have shown that USP14 is involved in several canonical signaling pathways, correlating with cancer, neurodegenerative diseases, autophagy, immune responses, and viral infections. The activity of USP14 is tightly regulated to ensure its function in various cellular processes. Structural studies have demonstrated that free USP14 exists in an autoinhibited state with two surface loops, BL1 and BL2, partially hovering above and blocking the active site cleft binding to the C-terminus of ubiquitin. Hence, both proteasome-bound and phosphorylated forms of USP14 require the induction of conformational changes in the BL2 loop to activate its deubiquitinating function. Due to its intriguing roles in the stabilization of disease-causing proteins and oncology targets, USP14 has garnered widespread interest as a therapeutic target. In recent years, significant progress has been made on identifying inhibitors targeting USP14, despite the complexity and challenges in improving their selectivity and affinity for USP14. In particular, the crystal structures of USP14 complexed with IU1-series inhibitors revealed the underlying allosteric regulatory mechanism and enabled the further design of potent inhibitors. In this review, we summarize the current knowledge regarding the structure, regulation, pathophysiological function, and selective inhibition of USP14, including disease associations and inhibitor development.

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Inhibition of USP14 induces ER stress–mediated autophagy without apoptosis in lung cancer cell line A549

Cited by 15 publications

References 34 publications

The Protective Effect of Cyanidin‐3‐Glucoside on Myocardial Ischemia‐Reperfusion Injury through Ferroptosis

The Protective Effect of Cyanidin‐3‐Glucoside on Myocardial Ischemia‐Reperfusion Injury through Ferroptosis

Targeting Ubiquitin–Proteasome System With Copper Complexes for Cancer Therapy

USP14: Structure, Function, and Target Inhibition

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