p62/SQSTM1 is involved in caspase‐8 associated cell death induced by proteasome inhibitor MG132 in U87MG cells

Zeng, Ruixia; Zhang, Yibo; Fan, Yu Shan; Wu, Ge-Li

doi:10.1002/cbin.10311

Cited by 20 publications

(16 citation statements)

References 23 publications

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“…Thus, the upregulation of SQSTM1 may make larger amounts of BECN1 available to start the autophagic pathway; to date, the role of SQSTM1 phosphorylation in this process is not well understood. Furthermore, upon clustering in aggregates, SQSTM1 has been shown to trigger the apoptosis cascade by recruiting and activating caspase-8 [58,59]. Although the upregulation of unphosphorylated SQSTM1 may not be the only entry point for RARA-induced worsening of mTBK1-associated autophagy impairment (considering the large number of genes modified by RARA in the human genome) and reduced MNs survival, it may nevertheless play a significant part in the process; in fact, mutations in SQSTM1 are causally linked to ALS [60], and pathogenic mutations in SQSTM1 have been shown to affect the binding of SQSTM1 with KEAP1 [61].…”

Section: Discussionmentioning

confidence: 99%

Retinoic acid worsens ATG10-dependent autophagy impairment in TBK1-mutant hiPSC-derived motoneurons through SQSTM1/p62 accumulation

Catanese

Heuvel

Mulaw³

et al. 2019

Autophagy

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Mutations in the TBK1 (TANK binding kinase 1) gene are causally linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TBK1 phosphorylates the cargo receptors OPTN and SQSTM1 regulating a critical step in macroautophagy/autophagy. Disruption of the autophagic flux leads to accumulation of cytosolic protein aggregates, which are a hallmark of ALS. hiPSC-derived TBK1-mutant motoneurons (MNs) showed reduced TBK1 levels and accumulation of cytosolic SQSTM1-positive aggresomes. By screening a library of nuclear-receptor-agonists for modifiers of the SQSTM1 aggregates, we identified 4-hydroxy-(phenyl)retinamide (4HPR) as a potent modifier exerting detrimental effects on mutant-TBK1 motoneurons fitness exacerbating the autophagy overload. We have shown by TEM that TBK1-mutant motoneurons accumulate immature phagophores due a failure in the elongation phase, and 4HPR further worsens the burden of dysfunctional phagophores. 4HPR-increased toxicity was associated with the upregulation of SQSTM1 in a context of strongly reduced ATG10, while rescue of ATG10 levels abolished 4HPR toxicity. Finally, we showed that 4HPR leads to a downregulation of ATG10 and to an accumulation of SQSTM1 + aggresomes also in hiPSC-derived C9orf72-mutant motoneurons. Our data show that cultured human motoneurons harboring mutations in TBK1 gene display typical ALS features, like decreased viability and accumulation of cytosolic SQSTM1-positive aggresomes. The retinoid 4HPR appears a strong negative modifier of the fitness of TBK1 and C9orf72-mutant MNs, through a pathway converging on the mismatch of initiated autophagy and ATG10 levels. Thus, autophagy induction appears not to be a therapeutic strategy for ALS unless the specific underlying pathway alterations are properly addressed.

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Section: Discussionmentioning

confidence: 99%

Retinoic acid worsens ATG10-dependent autophagy impairment in TBK1-mutant hiPSC-derived motoneurons through SQSTM1/p62 accumulation

Catanese

Heuvel

Mulaw³

et al. 2019

Autophagy

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“…We speculate that in SKOV3/DDP cells the escape from apoptosis was partly dependent on the activation of p62‐RIPK1‐NF‐κB survival pathway under the stress of chemotherapy. However, overexpression of the multi‐functional p62 protein is likely to have pleiotropic effects . Furthermore, p62 may also function as a switch that regulates opposing pathways depending on its interaction with different molecules in physiological and pathological conditions.…”

Section: Discussionmentioning

confidence: 99%

p62/SQSTM1 as an oncotarget mediates cisplatin resistance through activating RIP1‐NF‐κB pathway in human ovarian cancer cells

Yan

Zhang

et al. 2017

Cancer Science

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Platinum‐based therapeutic strategies have been widely used in ovarian cancer treatment. However, drug resistance has greatly limited therapeutic efficacy. Recently, tolerance to cisplatin has been attributed to other factors unrelated to DNA. p62 (also known as SQSTM1) functions as a multifunctional hub participating in tumorigenesis and may be a therapeutic target. Our previous study showed that p62 was overexpressed in drug‐resistant ovarian epithelial carcinoma and its inhibition increased the sensitivity to cisplatin. In this study, we demonstrate that the activity of the NF‐κB signaling pathway and K63‐linked ubiquitination of RIP1 was higher in cisplatin‐resistant ovarian (SKOV3/DDP) cells compared with parental cells. In addition, cisplatin resistance could be reversed by inhibiting the expression of p62 using siRNA. Furthermore, deletion of the ZZ domain of p62 that interacts with RIP1 in SKOV3 cells markedly decreased K63‐linked ubiquitination of RIP1 and inhibited the activation of the NF‐κB signaling pathway. Moreover, loss of the ZZ domain from p62 led to poor proliferative capacity and high levels of apoptosis in SKOV3 cells and made them more sensitive to cisplatin treatment. Collectively, we provide evidence that p62 is implicated in the activation of NF‐κB signaling that is partly dependent on RIP1. p62 promotes cell proliferation and inhibits apoptosis thus mediating drug resistance in ovarian cancer cells.

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“…Recently, high p62 cytoplasmic expression was shown to be associated with poor prognosis; conversely, other investigators have indicated that p62 is positively correlated with cell death. For example, proteasome inhibitor MG132 was reported to promote apoptosis of U87 cells through p62 accumulation and metastatic and recurrent tumour tissues express low levels of p62 . Our previous study found that p62 was involved in regulating the SKOV3 ovarian cancer cells sensitivity to chemotherapy through NF‐κB signalling and ubiquitin clearance .…”

Section: Introductionmentioning

confidence: 99%

p62 aggregates mediated Caspase 8 activation is responsible for progression of ovarian cancer

Yan

Zhong

et al. 2019

J Cellular Molecular Medi

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Increasing evidence suggests that p62/SQSTM1 functions as a signalling centre in cancer. However, the role of p62 in tumour development depends on the interacting factors it recruits and its precise regulatory mechanism remains unclear. In this study, we investigated the pro‐death signalling recruitment of p62 with the goal of improving anti‐tumour drug effects in ovarian cancer treatment. We found that p62 with Caspase 8 high expression is correlated with longer survival time compared with cases of low Caspase 8 expression in ovarian cancer. In vivo experiments suggested that insoluble p62 and ubiquitinated protein accumulation induced by autophagy impairment promoted the activation of Caspase 8 and increased cell sensitivity to cisplatin. Furthermore, p62 functional domain UBA and LIR mutants regulated autophagic flux and attenuated Caspase 8 activation, which indicates that autophagic degradation is involved in p62‐mediated activation of Caspase 8 in ovarian cancer cells. Collectively, our study demonstrates that p62 promotes Caspase 8 activation through autophagy flux blockage with cisplatin treatment. We have provided evidence that autophagy induction followed by its blockade increases cell sensitivity to chemotherapy which is dependent on p62‐Caspase 8 mediated apoptosis signalling. p62 exhibits pro‐death functions through its interaction with Caspase 8. p62 and Caspase 8 may become novel prognostic biomarkers and oncotargets for ovarian cancer treatment.

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p62/SQSTM1 is involved in caspase‐8 associated cell death induced by proteasome inhibitor MG132 in U87MG cells

Cited by 20 publications

References 23 publications

Retinoic acid worsens ATG10-dependent autophagy impairment in TBK1-mutant hiPSC-derived motoneurons through SQSTM1/p62 accumulation

Retinoic acid worsens ATG10-dependent autophagy impairment in TBK1-mutant hiPSC-derived motoneurons through SQSTM1/p62 accumulation

p62/SQSTM1 as an oncotarget mediates cisplatin resistance through activating RIP1‐NF‐κB pathway in human ovarian cancer cells

p62 aggregates mediated Caspase 8 activation is responsible for progression of ovarian cancer

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