A close connection between the PERK and IRE arms of the UPR and the transcriptional regulation of autophagy

Deegan, Shane; Koryga, Izabela; Glynn, Sharon A.; Gupta, Sanjeev; Gorman, Adrienne M.; Samali, Afshin

doi:10.1016/j.bbrc.2014.11.076

Cited by 50 publications

(56 citation statements)

References 17 publications

(13 reference statements)

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“…21,22 ERS is also implicated as a transcriptional driver of autophagy. 23 In this study, we show that riluzole activates ERS specifically via ATF6α and IRE1α signaling arms, promoting autophagy and interaction between AR and the selective autophagy receptor p62. We also demonstrate that activation of IRE1α is required for riluzole-induced AR degradation.…”

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confidence: 53%

“…Activating transcription factor‐6α (ATF6α), inositol‐requiring protein‐1α (IRE1α), and protein kinase RNA‐like ER kinase (PERK) are ER membrane proteins which activate the three signaling arms of ERS and the downstream UPR (Figure S1) . ERS is also implicated as a transcriptional driver of autophagy . In this study, we show that riluzole activates ERS specifically via ATF6α and IRE1α signaling arms, promoting autophagy and interaction between AR and the selective autophagy receptor p62.…”

Section: Introductionmentioning

confidence: 72%

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Riluzole induces AR degradation via endoplasmic reticulum stress pathway in androgen‐dependent and castration‐resistant prostate cancer cells

et al. 2018

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Background Prostate cancer (PCa) is diagnosed at the highest rate of all non‐cutaneous male cancers in the United States. The androgen‐dependent (AD) transcription factor, androgen receptor (AR), drives PCa—but inhibiting AR or androgen biosynthesis induces remission for only a short time. At which point, patients acquire more aggressive castration‐resistant (CR) disease with re‐activated AR‐dependent signaling. To combat treatment resistance, down‐regulating AR protein expression has been considered as a potential treatment strategy for CR‐PCa. Methods AD‐ and CR‐PCa cell lines were treated with the well‐tolerated FDA‐approved oral medicine, riluzole. Expression of full‐length or wild‐type AR (AR‐FL) and constitutively active AR‐splice variant 7 (AR‐V7) was assessed by immunoblotting. AR‐FL/AR‐V7 activity was measured using qRT‐PCR of AR‐target genes. Cytoplasmic [Ca2+] levels were measured using a fluorescent Ca2+ indicator microplate assay. Markers of the endoplasmic reticulum stress (ERS) pathway and autophagy were assessed by immunoblotting. Direct interaction between AR and selective autophagy receptor p62 was demonstrated by co‐immunoprecipitation. Results We demonstrate that riluzole downregulates AR‐FL, mutant ARs, and AR‐V7 proteins expression by protein degradation through ERS pathway and selective autophagy. Riluzole also significantly inhibited AR transcription activity by decreasing its target genes expression (PSA, TMPRSS2, and KLK2). Conclusions We provide key mechanistic insights by which riluzole exerts its anti‐tumorigenic effects and induces AR protein degradation via ERS pathways. Our findings support the potential utility of riluzole for treatment of PCa.

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confidence: 53%

Section: Introductionmentioning

confidence: 72%

Riluzole induces AR degradation via endoplasmic reticulum stress pathway in androgen‐dependent and castration‐resistant prostate cancer cells

et al. 2018

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“…Accumulating unfolded proteins in the ER causes ERS and triggers activation of the UPR . At least three ER transmembrane sensor proteins are activated, including PERK , ATF6 and IRE1 . Under continuous ERS, the UPR can be triggered as a prosurvival process through the transient termination of translation, the induction of a large number of proteins that coordinately function to renature unfolded proteins.…”

Section: Resultsmentioning

confidence: 99%

Magnesium isoglycyrrhizinate promotes the activated hepatic stellate cells apoptosis via endoplasmic reticulum stress and ameliorates fibrogenesis in vitro and in vivo

et al. 2017

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Varied pathogenetic elements have been touched upon the liver fibrosis, including inflammatory, stress, apoptosis and unfolded proteins aggregation. Magnesium Isoglycyrrhizinate (MgIG) has been accepted to be a neuroprotective effect, hepatoprotective and anti-inflammatory molecule. In our vitro researches, MgIG was considered to activate hepatic stellate cells (HSCs) apoptosis by promoting endoplasmic reticulum stress (ERS) detrimental response to a certain extent. Consequently, MgIG showed its potential therapeutic capacity in fibrogenesis and counteracted the pathogenetic aspects, which were involved in integrating current treatments correcting liver fibrosis. In addition, we further verificated the behavior and pathogenic mechanisms in the CCl -induced liver fibrosis in male mice. What surprised us was that with the treatment of MgIG caused the activation of ERS and resisted the activated HSCs in the protective effects on liver damage. We found MgIG significantly promoted the apoptosis of activated HSCs and protected the CCl -induced liver fibrosis. Main molecules came down to the unfolded protein response signaling pathway. Furthermore, MgIG inhibited the levels of the downstream inflammatory cytokines, which were triggered by CCl -induced liver fibrosis. Here, we reported that MgIG improved behavioral impairments induced by intraperitoneal injection of CCl and decreased the expression of proinflammatory factor, which indicated the preserving effects on liver fibrosis. © 2017 BioFactors, 43(6):836-846, 2017.

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“…Previous studies have shown that ER stress-activated genes mediated by the unfolded protein response (UPR, PERK, ATF6, and IRE1) are involved in autophagy [37, 38] or apoptosis [39, 40] in several cancers. Furthermore, JNK activation is also involved in autophagy induction in several cancers [41] through close association with ER stress [42].…”

Section: Discussionmentioning

confidence: 99%

Activation of JNK and IRE1 is critically involved in tanshinone I-induced p62 dependent autophagy in malignant pleural mesothelioma cells: implication of p62 UBA domain

et al. 2017

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The aim of present study is to elucidate autophagic mechanism of tanshinone I (Tan I) in H28 and H2452 mesothelioma cells. Herein, Tan I exerted cytotoxicity with autophagic features of autophagy protein 5 (ATG5)/ microtubule-associated protein 1A/1B-light chain 3II (LC3 II) activation, p62/sequestosome 1 (SQSTM1) accumulation and increased number of LC3II punctae, acridine orange-stained cells and autophagic vacuoles. However, 3-methyladenine (3MA) and NH4Cl increased cytotoxicity in Tan I treated H28 cells. Furthermore, autophagy flux was enhanced in Tan I-treated H28 cells transfected by RFP-GFP-LC3 constructs, with colocalization of GFP-LC3 punctae with LAMP1 or Lysotracker. Interestingly, C-terminal UBA domain is required for Tan 1 induced aggregation of p62 in H28 cells. Notably, Tan I upregulated CCAAT-enhancer-binding protein homologous protein (CHOP), inositol-requiring protein-1 (IRE1) and p-c-Jun N-terminal kinase (p-JNK), but silencing of IRE1 or p62 and JNK inhibitor SP600125 blocked the LC3II accumulation in Tan I-treated H28 cells. Overall, these findings demonstrate that Tan I exerts antitumor activity through a compromise between apoptosis and p62/SQSTM1-dependent autophagy via activation of JNK and IRE 1 in malignant mesothelioma cells.

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A close connection between the PERK and IRE arms of the UPR and the transcriptional regulation of autophagy

Cited by 50 publications

References 17 publications

Riluzole induces AR degradation via endoplasmic reticulum stress pathway in androgen‐dependent and castration‐resistant prostate cancer cells

Riluzole induces AR degradation via endoplasmic reticulum stress pathway in androgen‐dependent and castration‐resistant prostate cancer cells

Magnesium isoglycyrrhizinate promotes the activated hepatic stellate cells apoptosis via endoplasmic reticulum stress and ameliorates fibrogenesis in vitro and in vivo

Activation of JNK and IRE1 is critically involved in tanshinone I-induced p62 dependent autophagy in malignant pleural mesothelioma cells: implication of p62 UBA domain

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