p62/SQSTM1, a Central but Unexploited Target: Advances in Its Physiological/Pathogenic Functions and Small Molecular Modulators

Chen, Ying; Li, Qi; Li, Qihang; Xing, Shuaishuai; Liu, Yang; Liu, Yijun; Chen, Yao; Liu, Wenyuan; Feng, Feng; Sun, Haopeng

doi:10.1021/acs.jmedchem.9b02038

Cited by 33 publications

(18 citation statements)

References 210 publications

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“…The level of p62 is widely used as an indicator of autophagic flux. Suppression or decline of autophagy is always accompanied by the accumulation of p62 (Chen et al, 2020). We observed the morphology and structure of autophagic vesicles using transmission electron microscopy, and found that morphine tolerance induced the ac- Minocycline, a tetracycline antibiotic, has immunomodulatory effects beyond its antibacterial activity, including anti-inflammatory, anti-apoptotic and neuroprotective properties (Garrido-Mesa et al, 2013;Tikka & Koistinaho, 2001;Wang et al, 2003).…”

Section: Discussionmentioning

confidence: 91%

“…The level of p62 is widely used as an indicator of autophagic flux. Suppression or decline of autophagy is always accompanied by the accumulation of p62 (Chen et al., 2020). We observed the morphology and structure of autophagic vesicles using transmission electron microscopy, and found that morphine tolerance induced the accumulation of autophagic vacuoles in spinal cord.…”

Section: Discussionmentioning

confidence: 99%

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Activation of spinal PDGFRβ in microglia promotes neuronal autophagy via p38 MAPK pathway in morphine‐tolerant rats

Jia

Zhang

et al. 2021

Journal of Neurochemistry

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Morphine is the most potent analgesic in clinical treatment for various painful conditions. Long-term usage of morphine inevitably leads to the development of antinociceptive tolerance, which limits its clinical utilization (Christie, 2008;Wickham, 2017). For several decades, numerous studies have been devoted to illuminating the mechanisms underlying morphine tolerance, including nitric oxide-cyclic 3'-5' guanosine monophosphate signaling pathway, α 2 noradrenergic system cannabinoid system, and hyperexcitability of the central nervous system (Fisher et al., 2019;Gursoy et al., 2011;Ozdemir, 2020;Ozdemir et al., 2011). However, the neurobiological mechanisms of morphine tolerance are multifaceted and only partially understood.Macroautophagy, hereafter autophagy, is a lysosomal-dependent degradation pathway in eukaryotic cells, which is important for the generation of degradation products and intracellular clearance of defective macromolecules and organelles (Mizushima, 2018). Over the

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Activation of spinal PDGFRβ in microglia promotes neuronal autophagy via p38 MAPK pathway in morphine‐tolerant rats

Jia

Zhang

et al. 2021

Journal of Neurochemistry

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“…Previous study revealed that oligomerized p62 targeted to the autophagosome formation site independent of LC3 (25). A recent study showed that p62 protein expression was not associated with autophagy under specific conditions (26), while p62 protein has also been shown to promote tumor cell survival by activation of the NF-kb pathway (27). The latest study revealed that p62 expression might target PD-L1, and p62 signaling axis could be useful to suppress the EGFR-TKIresistant lung cancer (28).…”

Section: Discussionmentioning

confidence: 99%

p62 Overexpression Promotes Bone Metastasis of Lung Adenocarcinoma out of LC3-Dependent Autophagy

et al. 2021

Front. Oncol.

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p62 protein has been implicated in bone metastasis and is a multifunctional adaptor protein usually correlated with autophagy. Herein, we investigated p62 expression and its prognostic significance in bone metastasis of lung adenocarcinoma, and analyzed whether the mechanism involved depends on autophagy. mRNA and protein expression of p62, LC3B and Beclin 1 were detected by reverse transcription-quantitative PCR and western blotting, respectively, in fresh bone metastasis tissues (n=6 cases) and normal cancellous bone tissues (n=3 cases). The association between p62 and LC3B expression and patient prognosis was subsequently analyzed in 62 paraffin-embedded bone metastasis specimens by immunohistochemistry assay. Small interfering RNA (siRNA) was employed to downregulate p62 expression in SPC-A-1 and A549 cells. Cell proliferation and migration ability were tested by CCK8, CCF and Transwell assays respectively. Autophagy was induced by Rapamycin or inhibited by Atg 7 knockout/Chloroquine in A549 cells and p62 and LC3II/I expression were analyzed. After subcutaneous inoculation or intracardial injection of A549 cells into nude mice, the effect of p62 downregulation in vivo was analyzed by histopathological examination. The results showed that p62, LC3B and Beclin 1 mRNA and protein were all overexpressed in bone metastasis tissues (all P<0.01). Patient samples with high p62 expression levels were significantly associated with more bone lesions (>3), shorter overall survival rates and shorter progression free survival rates compared with patients having lower p62 expression (P=0.014, P=0.003, P=0.048, respectively). Cox regression analysis identified p62 expression as an independent prognostic indicator of overall survival of patients with bone metastasis (P=0.007). In vitro p62 downregulation inhibited SPC-A-1 and A549 cells migration but had no effect on cell proliferation. After autophagy induction or inhibition, p62 expression involved in autophagy flux and changed inconsistently according to the switch of LC3I to LC3II in different autophagy conditions. In vivo p62 downregulation had no effect on growth of subcutaneous tumor. Lung or bone metastasis lesion was not found in all mice model. These findings suggested that p62 overexpression promotes tumor cell invasion out of LC3-dependent autophagy, which could be used a potential prognostic biomarker and therapeutic target for bone metastasis of lung adenocarcinoma.

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“…Oxidative Medicine and Cellular Longevity [71]. p62/SQSTM1 plays a crucial part in the oxidative stress response pathway through its direct association with the ubiquitin ligase adaptor Kelch-like ECH-associated protein 1 (Keap-1), resulting in Nrf2 activation [51].…”

Section: Discussionmentioning

confidence: 99%

Coenzyme Q0 Inhibits NLRP3 Inflammasome Activation through Mitophagy Induction in LPS/ATP-Stimulated Macrophages

Hseu

Tseng

Pandey

et al. 2022

Oxidative Medicine and Cellular Longevity

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Coenzyme Q (CoQ) analogs with a variable number of isoprenoid units have exhibited as anti-inflammatory as well as antioxidant molecules. Using novel quinone derivative CoQ0 (2,3-dimethoxy-5-methyl-1,4-benzoquinone, zero side chain isoprenoid), we studied its molecular activities against LPS/ATP-induced inflammation and redox imbalance in murine RAW264.7 macrophages. CoQ0’s non- or subcytotoxic concentration suppressed the NLRP3 inflammasome and procaspase-1 activation, followed by downregulation of IL1β expression in LPS/ATP-stimulated RAW264.7 macrophages. Similarly, treatment of CoQ0 led to LC3-I/II accumulation and p62/SQSTM1 activation. An increase in the Beclin-1/Bcl-2 ratio and a decrease in the expression of phosphorylated PI3K/AKT, p70 S6 kinase, and mTOR showed that autophagy was activated. Besides, CoQ0 increased Parkin protein to recruit damaged mitochondria and induced mitophagy in LPS/ATP-stimulated RAW264.7 macrophages. CoQ0 inhibited LPS/ATP-stimulated ROS generation in RAW264.7 macrophages. Notably, when LPS/ATP-stimulated RAW264.7 macrophages were treated with CoQ0, Mito-TEMPO (a mitochondrial ROS inhibitor), or N-acetylcysteine (NAC, a ROS inhibitor), there was a significant reduction of LPS/ATP-stimulated NLRP3 inflammasome activation and IL1β expression. Interestingly, treatment with CoQ0 or Mito-TEMPO, but not NAC, significantly increased LPS/ATP-induced LC3-II accumulation indicating that mitophagy plays a key role in the regulation of CoQ0-inhibited NLRP3 inflammasome activation. Nrf2 knockdown significantly decreased IL1β expression in LPS/ATP-stimulated RAW264.7 macrophages suggesting that CoQ0 inhibited ROS-mediated NLRP3 inflammasome activation and IL1β expression was suppressed due to the Nrf2 activation. Hence, this study showed that CoQ0 might be a promising candidate for the therapeutics of inflammatory disorders due to its effective anti-inflammatory as well as antioxidant properties.

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p62/SQSTM1, a Central but Unexploited Target: Advances in Its Physiological/Pathogenic Functions and Small Molecular Modulators

Cited by 33 publications

References 210 publications

Activation of spinal PDGFRβ in microglia promotes neuronal autophagy via p38 MAPK pathway in morphine‐tolerant rats

Activation of spinal PDGFRβ in microglia promotes neuronal autophagy via p38 MAPK pathway in morphine‐tolerant rats

p62 Overexpression Promotes Bone Metastasis of Lung Adenocarcinoma out of LC3-Dependent Autophagy

Coenzyme Q0 Inhibits NLRP3 Inflammasome Activation through Mitophagy Induction in LPS/ATP-Stimulated Macrophages

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