p62/SQSTM1 is required for the protection against endoplasmic reticulum stress-induced apoptotic cell death

Park, Jeong Su; Oh, Sejong; Lee, Da Hyun; Lee, Yu Seol; Sung, Su Haeng; Ji, Hye Won; Lee, Moonjoo; Lee, Yong-Ho; Rhee, Sue Goo; Bae, Soo Han

doi:10.1080/10715762.2016.1253073

Cited by 23 publications

(15 citation statements)

References 39 publications

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“…In recent years, there are many reports showing that p62–Keap1–Nrf2 pathway plays a protective role in oxidative and stress conditions. For example, ER stress-induced apoptosis is prevented by the activation of p62–Keap1–Nrf2 pathway ( 64 ). Quercetin attenuates the hepatotoxicity induced by a various hepatotoxicants, through the activation of p62–Keap1–Nrf2 pathway ( 65 ).…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Activation of p62/SQSTM1–Keap1–Nuclear Factor Erythroid 2-Related Factor 2 Pathway in Cancer

Ichimura

Komatsu

2018

Front. Oncol.

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Autophagy and the Keap1–Nrf2 system are major cellular defense mechanisms against metabolic and oxidative stress. These two systems are linked via phosphorylation of the ubiquitin binding autophagy receptor protein p62/SQSTM1 in the p62–Keap1–Nrf2 pathway. The p62–Keap1–Nrf2 pathway plays a protective role in normal cells; however, recent studies indicate that this pathway induces tumorigenesis of pre-malignant cells, and promotes the growth and drug resistance of tumor cells via metabolic reprogramming mediated by Nrf2 activation. These findings suggest that impairment of autophagy is involved in the acquisition of malignancy and maintenance of tumors, and furthermore, that p62/SQSTM1 could be a potential target for chemotherapy in cancers that harbor excess p62.

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Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Activation of p62/SQSTM1–Keap1–Nuclear Factor Erythroid 2-Related Factor 2 Pathway in Cancer

Ichimura

Komatsu

2018

Front. Oncol.

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“…Furthermore, the potential biological processes mainly involved in regulation of endoplasmic reticulum unfolded protein response has also been discussed. Unfolded protein response (UPR) is a protective cellular response activated by endoplasmic reticulum stress (31). SQSTM1 was known to protect cells against tunicamycin (TM)-mediated oxidative damage through Nrf2 activation (32,33).…”

Section: Discussionmentioning

confidence: 99%

Prognostic Significance of SQSTM1 in Breast Cancer: A Comprehensive Analysis

Liu

Sun

et al. 2020

Preprint

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Background: SQSTM1 (Sequestosome 1, p62) is degraded by activated autophagy and involved in the progression of in various types of cancers. However, the prognostic role and underlying regulation mechanism of SQSTM1 in the progression and development of breast cancer remain unclear.Methods: In this study, 1336 samples with available mRNA data from Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) database and 27 formalin fixation and paraffin embedding (FFPE) tissue samples from the First Affiliated Hospital of Xi’an Jiaotong University were collected to evaluate SQSTM1 expression in mRNA and protein levels. Kaplan–Meier and Cox regression were used for revealing prognostic value in three independent breast cancer independent datasets. Tumor Immune Estimation Resource (TIMER) database and Gene Set Variation Analysis (GSVA) was used to explore the relationship of SQSTM1 mRNA expression and immune infiltration level in breast cancer. Dysregulation mechanisms of SQSTM1 were also explored including copy number variation (CNV), somatic mutation, epigenetic alterations and other transcription and post-transcription level using multiple datasets. Finally, Gene Set Enrichment Analysis (GSEA) was constructed to elucidate functional regulating performance of SQSTM1 in breast cancer.Results: The results showed that mRNA and protein level of SQSTM1 were significantly elevated in breast cancer and receiver operating characteristic (ROC) curve showed that p62 may act as diagnostic biomarker. Lower expression of SQSTM1 predicted better outcome through multiple datasets. It was also found that SQSTM1 correlated with immune infiltrates in breast cancer. Moreover, CNV and methylation of SQSTM1 DNA was correlated with SQSTM1 dysregulation and act as prognostic factors for breast cancer patients. Yet, somatic mutation status of SQSTM1 didn’t show any prognostic relevance. We also identified diverse transcription factors that directly bound to SQSTM1 DNA and the miRNAs which may regulate SQSTM1 mRNA. Finally, functional enrichment analysis revealed that SQSTM1 is related to cell signal transduction, oxidative stress and autophagy in breast cancer.Conclusion: Our findings revealed that overexpression of SQSTM1 significantly to poor survival and immune infiltrations in breast cancer. In addition, SQSTM1 plays a key role in the progression of breast cancer and might be a promising biomarker for the diagnosis and personalized treatment of breast cancer patients.

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“…Moreover, in COPD-emphysema studies, smoking has been implicated in mediating autophagy-impairment and the peri-nuclear accumulation of ubiquitinated proteins as aggresome bodies that correlates with the severity of emphysema in COPD subjects [ 17 , 20 , 27 ]. It has also been well documented that ROS can induce ER stress and result in misfolded protein accumulation and autophagy plays a key role in alleviating ROS and ER stress accumulation [ 11 , 37 , 38 ]. Therefore, we hypothesized that cigarette smoking directly contributes to AMD pathogenesis by inducing proteostasis/autophagy-impairment and subsequent peri-nuclear aggregation of ubiquitinated proteins in aggresome bodies.…”

Section: Discussionmentioning

confidence: 99%

Cigarette smoke induced autophagy-impairment regulates AMD pathogenesis mechanisms in ARPE-19 cells

2017

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Age related macular degeneration (AMD) is one of the leading causes of blindness. Genetics, environmental insult, and age-related factors all play a key role in altering proteostasis, the homeostatic process regulating protein synthesis, degradation and processing. These factors also play a role in the pathogenesis of AMD and it has been well established that cigarette smoking (CS) initiates AMD pathogenic mechanisms. The primary goal of this study is to elucidate whether CS can induce proteostasis/autophagy-impairment in retinal pigment epithelial (RPE) cells. In our preliminary analysis, it was found that cigarette smoke extract (CSE) induces accumulation of ubiquitinated proteins in the insoluble protein fraction (p < 0.01), which was subsequently mitigated through cysteamine (p < 0.01) or fisetin (p < 0.05) treatment. Further, it was verified that these CSE induced ubiquitinated proteins accumulated in the peri-nuclear spaces (p<0.05) that were cleared- off with cysteamine (p < 0.05) or fisetin (p < 0.05). Moreover, CSE-induced aggresome-formation (LC3B-GFP and Ub-RFP co-localization) and autophagy-flux impairment was significantly (p<0.01) mitigated by cysteamine (p<0.05) or fisetin (p<0.05) treatment, indicating the restoration of CSE-mediated autophagy-impairment. CSE treatment was also found to induce intracellular reactive oxygen species (ROS, p < 0.001) while impacting cell viability (p < 0.001), which was quantified using CMH2DCFDA-dye (ROS) and MTS (proliferation) or propodium iodide staining (cell viability) assays, respectively. Moreover, cysteamine and fisetin treatment ameliorated CS-mediated ROS production (p < 0.05) and diminished cell viability (p < 0.05). Lastly, CSE was found to induce cellular senescence (p < 0.001), which was significantly ameliorated by cysteamine (p < 0.001) or fisetin (p < 0.001). In conclusion, our study indicates that CS induced proteostasis/autophagy-impairment regulates mechanisms associated with AMD pathogenesis. Moreover, autophagy-inducing drugs such as cysteamine or fisetin can ameliorate AMD pathogenesis mechanisms that warrant further investigation in pre-clinical murine models.

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p62/SQSTM1 is required for the protection against endoplasmic reticulum stress-induced apoptotic cell death

Cited by 23 publications

References 39 publications

Activation of p62/SQSTM1–Keap1–Nuclear Factor Erythroid 2-Related Factor 2 Pathway in Cancer

Activation of p62/SQSTM1–Keap1–Nuclear Factor Erythroid 2-Related Factor 2 Pathway in Cancer

Prognostic Significance of SQSTM1 in Breast Cancer: A Comprehensive Analysis

Cigarette smoke induced autophagy-impairment regulates AMD pathogenesis mechanisms in ARPE-19 cells

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