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1.
Mol Biol Rep ; 49(11): 11061-11070, 2022 Nov.
Article in English | MEDLINE | ID: mdl-36097120

ABSTRACT

Parkinson's disease (PD) is one of the most common neurological diseases, next only to Alzheimer's disease (AD) in terms of prevalence. It afflicts about 2-3% of individuals over 65 years old. The etiology of PD is unknown and several environmental and genetic factors are involved. From a pathological point of view, PD is characterized by the loss of dopaminergic neurons in the substantia nigra, which causes the abnormal accumulation of α-synuclein (α-syn) (a component of Lewy bodies), which subsequently interact with heat shock proteins (HSPs), leading to apoptosis. Apoptosis is a vital pathway for establishing homeostasis in body tissues, which is regulated by pro-apoptotic and anti-apoptotic factors. Recent findings have shown that HSPs, especially HSP27 and HSP70, play a pivotal role in regulating apoptosis by influencing the factors involved in the apoptosis pathway. Moreover, it has been reported that the expression of these HSPs in the nervous system is high. Apart from this finding, investigations have suggested that HSP27 and HSP70 (related to parkin) show a potent protective and anti-apoptotic impact against the damaging outcomes of mutant α-syn toxicity to nerve cells. Therefore, in this study, we aimed to investigate the relationship between these HSPs and apoptosis in patients with PD.


Subject(s)
Parkinson Disease , alpha-Synuclein , Humans , Aged , alpha-Synuclein/genetics , alpha-Synuclein/metabolism , Parkinson Disease/genetics , Parkinson Disease/metabolism , HSP27 Heat-Shock Proteins/genetics , Heat-Shock Proteins/genetics , Heat-Shock Proteins/metabolism , HSP70 Heat-Shock Proteins/genetics , Dopaminergic Neurons/metabolism , Ubiquitin-Protein Ligases/genetics
2.
Cell Stress Chaperones ; 25(6): 909-917, 2020 11.
Article in English | MEDLINE | ID: mdl-32632734

ABSTRACT

Non-small cell lung cancer is the most common type of lung cancer, accounting for more than 80% of this tumor. Ubiquitin-specific protease (USP) 14 is one of the 100 deubiquitinating enzymes that is overexpressed in lung cancer and has been validated as a therapeutic target. The aim of this study is to determine whether the accumulation of ubiquitinated proteins results in endoplasmic reticulum (ER) stress-mediated autophagy. To inhibit USP-14, A549 lung cancer cells were treated with USP-14 siRNA and IU1-47 (20 µM). The protein level, mRNA expression, and cell cycle analysis were evaluated using Western blot, real-time PCR, and flow cytometry, respectively. We found that treating A549 cells with USP14 inhibitors significantly reduced the proliferation rate and induced cell cycle arrest at G2/M phase. We also found that USP14 inhibitors did not induce apoptosis but actually induced autophagy through accumulation of ubiquitinated proteins/ER stress/unfolded protein response (UPR) axis. Moreover, we have for the first time demonstrated that the USP14 inhibition induces ER stress-mediated autophagy in A549 cells by activation of c-Jun N-terminal kinase 1 (JNK1). In conclusion, the current investigation represents a new mechanism by which inhibition of USP14 triggers autophagy via ER stress-mediated UPR in A549 cells.


Subject(s)
Apoptosis , Autophagy , Endoplasmic Reticulum Stress , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Ubiquitin Thiolesterase/antagonists & inhibitors , A549 Cells , Biomarkers, Tumor/metabolism , Cell Cycle Checkpoints , Cell Proliferation , Cell Survival , Humans , Ubiquitin Thiolesterase/metabolism , Ubiquitinated Proteins/metabolism
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