Targeting of endoplasmic reticulum (ER) stress in gliomas

Markouli, Mariam; Strepkos, Dimitrios; Papavassiliou, Athanasios G.; Piperi, Christina

doi:10.1016/j.phrs.2020.104823

Cited by 45 publications

(29 citation statements)

References 111 publications

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“…We found that homocysteine remarkably upregulates GRP78 both in vivo and in vitro and GRP78 promoted ER stress-mediated apoptosis induced by homocysteine, which is consisitent with previous reports. Interestingly, the recent discovery that cannabidiol causes activated hepatic satellite cell death through a mechanism of ER stress-induced apoptosis (23), which further con rmed our results that homocysteine promotes ER stress-mediated apoptosis to induce liver injury.…”

Section: Discussionsupporting

confidence: 88%

Down-Regulation of miR-212-5p Facilitates Homocysteine-Induced Hepatocytes Apoptosis Via Targeting PSMD10

Zhang¹,

Xiao²,

Ma³

et al. 2020

Preprint

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Background: Increasing evidences supported that elevated homocysteine (Hcy) levels contribute to cell apoptosis is implicated in the pathogenesis of liver injury, it correlates with liver disease severity. However, the underlying mechanism of apoptosis in Hcy-mediated liver injury remains obscure. Results: In this study, we found that homocysteine increases ER stress-mediated apoptosis and aggravates liver injury through up-regulation of PSMD10 expression in cbs+/- mice mice fed with high methionine diet and hepatocytes treated with homocysteine in vitro. Knockdown of PSMD10 expression remarkably reduced ER stress or apoptosis-associated protein in hepatocytes exposed to homocysteine. Moreover, bioinformatics analysis revealed that PSMD10 is a potential target gene of miR-212-5p, and luciferase reporter assay also confirmed that miR-212-5p negatively regulated PSMD10 expression by direct binding to its 3’-UTR regions. Subsequently, over-expression of miR-212-5p inhibited ER stress-mediated hepatocytes apoptosis though targeting PSMD10, all of which were abrogated by knockdown of miR-212-5p expression. Further study showed that the interaction between PSMD10 and GRP78 accelerated ER stress-mediated hepatic apoptosis induced by homocysteine. Conclusion: Taken together, these results demonstrated that down-regulation of miR-212-5p facilitates homocysteine-induced hepatocytes apoptosis via targeting PSMD10, which provides novel insight into the mechanism of homocysteine induced apoptosis in liver injury.

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Section: Discussionsupporting

confidence: 88%

Down-Regulation of miR-212-5p Facilitates Homocysteine-Induced Hepatocytes Apoptosis Via Targeting PSMD10

Zhang¹,

Xiao²,

Ma³

et al. 2020

Preprint

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“…In the inactivated state, cells block PERK, IRE1α, and ATF6 sensor receptors through the molecular chaperone protein GRP78 (also known as BiP). When endoplasmic reticulum stress is activated, the association is disrupted and the UPR signal transduction cascade commences [ 10 , 11 ]. It is worth noting that UPR plays a dual function in tumor cells, i.e., if it cannot effectively control endoplasmic reticulum stress and restore proteostasis, then it will initiate apoptosis [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

RETRACTED ARTICLE: GRP78 determines glioblastoma sensitivity to UBA1 inhibition-induced UPR signaling and cell death

Liu

et al. 2021

Cell Death Dis

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Glioblastoma multiforme (GBM) is an extremely aggressive brain tumor for which new therapeutic approaches are urgently required. Unfolded protein response (UPR) plays an important role in the progression of GBM and is a promising target for developing novel therapeutic interventions. We identified ubiquitin-activating enzyme 1 (UBA1) inhibitor TAK-243 that can strongly induce UPR in GBM cells. In this study, we evaluated the functional activity and mechanism of TAK-243 in preclinical models of GBM. TAK-243 significantly inhibited the survival, proliferation, and colony formation of GBM cell lines and primary GBM cells. It also revealed a significant anti-tumor effect on a GBM PDX animal model and prolonged the survival time of tumor-bearing mice. Notably, TAK-243 more effectively inhibited the survival and self-renewal ability of glioblastoma stem cells (GSCs) than GBM cells. Importantly, we found that the expression level of GRP78 is a key factor in determining the sensitivity of differentiated GBM cells or GSCs to TAK-243. Mechanistically, UBA1 inhibition disrupts global protein ubiquitination in GBM cells, thereby inducing ER stress and UPR. UPR activates the PERK/ATF4 and IRE1α/XBP signaling axes. These findings indicate that UBA1 inhibition could be an attractive strategy that may be potentially used in the treatment of patients with GBM, and GRP78 can be used as a molecular marker for personalized treatment by targeting UBA1.

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“…That said, we then turned to evaluate the effects of DHE and BRA-346 epoxyketone-containing fraction on genes related to pathways that showed modulation of ER-stress response in gliomas (Markouli et al, 2020). While notable differences were observed between responses elicited by each cell line, a similar molecular profile, in which most of the assessed genes were found to be upregulated by both DHE and the BRA-346 epoxyketonecontaining fraction was revealed, reflecting a compensatory mechanism undergoing in cells exposed to either treatment to overcome ER disturbances (Kadowaki and Nishitoh, 2013).…”

Section: Discussionmentioning

confidence: 99%

Marine Streptomyces sp. Isolated From the Brazilian Endemic Tunicate Euherdmania sp. Produces Dihydroeponemycin and Analogs With Potent Antiglioma Activity

et al. 2021

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Marine natural products have emerged as an important source for drug development, notably in the field of anticancer therapy. Still, the limited effectiveness of current therapies for central nervous system tumors indicates the need to identify new therapeutic targets and also novel pharmacological agents. In this context, proteasome inhibitors are appearing as a promising new treatment for these diseases. Herein, cytotoxic extracts produced by four marine bacteria recovered from the Brazilian endemic ascidian Euherdmania sp. were screened to evaluate their potential as proteasome inhibitors. The extract from marine Streptomyces sp. BRA-346 was selected for further investigation due to the potent proteasome inhibitory activity it displayed. Bioassay-guided fractionation led to an enriched fraction (proteasome inhibition IC50 = 45 ng/mL), in which the presence of dihydroeponemycin (DHE), known for its proteasome inhibitory effect, and related compounds were annotated by mass spectrometry and further confirmed by comparison with DHE standard. Both DHE and the epoxyketone-containing fraction were evaluated in glioma cell lines, displaying high cytotoxicity in HOG and T98G cells (GI50 of 1.6 and 1.7 ng/mL for DHE, and 17.6 and 28.2 ng/mL for the BRA-346 fraction, respectively). Additional studies showed that the epoxyketone-containing fraction (at GI50 levels) led to an accumulation of ubiquitinated proteins and up-regulation of genes related to ER-stress response, suggesting treated cells are under proteasome inhibition. DHE induced similar effects in treated cells but at concentrations 25 times its GI50, suggesting that the other epoxyketone compounds in the bacteria extract derived fraction may contribute to enhance proteasome inhibition and further cellular effects in glioma cells. These findings revealed the molecular pathways modulated by this class of compounds in glioma cells and, moreover, reinforced the potential of this marine bacteria in producing a cocktail of structurally-related compounds that affect the viability of glioma cells.

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Targeting of endoplasmic reticulum (ER) stress in gliomas

Cited by 45 publications

References 111 publications

Down-Regulation of miR-212-5p Facilitates Homocysteine-Induced Hepatocytes Apoptosis Via Targeting PSMD10

Down-Regulation of miR-212-5p Facilitates Homocysteine-Induced Hepatocytes Apoptosis Via Targeting PSMD10

RETRACTED ARTICLE: GRP78 determines glioblastoma sensitivity to UBA1 inhibition-induced UPR signaling and cell death

Marine Streptomyces sp. Isolated From the Brazilian Endemic Tunicate Euherdmania sp. Produces Dihydroeponemycin and Analogs With Potent Antiglioma Activity

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