GRP78 translocation to the cell surface and O-GlcNAcylation of VE-Cadherin contribute to ER stress-mediated endothelial permeability

Lenin, Raji Rajesh; Nagy, Peter G.; Jha, Kumar Abhiram; Gangaraju, Rajashekhar

doi:10.1038/s41598-019-47246-w

Cited by 32 publications

(25 citation statements)

References 50 publications

(61 reference statements)

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“…O-GlcNAcylation is increased in various cellular stresses, including chemotherapy treatment and ER stress, directly influencing cell survival in cancer cells. It has been reported that DOX activates the HBP through the AKT/XBP axis, which can promote O-GlcNAcylation [42]. Moreover, a recent study has suggested that reducing O-GlcNAcylation in cancer cells leads to CHOP induction through the activation of the ER stress response, resulting in apoptosis [43].…”

Section: Discussionmentioning

confidence: 99%

O-GlcNAc Transferase Inhibitor Synergistically Enhances Doxorubicin-Induced Apoptosis in HepG2 Cells

Lee

Kwon

2020

Cancers

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The combination of chemotherapy with chemosensitizing agents is a common approach to enhance anticancer activity while reducing the dose-dependent adverse side effects of cancer treatment. Herein, we investigated doxorubicin (DOX) and O-GlcNAc transferase (OGT) inhibitor OSMI-1 combination treatment, which significantly enhanced apoptosis in hepatocellular carcinoma cells (HepG2) as a result of synergistic drug action in disparate stress signaling pathways. Treatment with a low dose of DOX or a suboptimal dose of OSMI-1 alone did not induce apoptotic cell death in HepG2 cells. However, the combination of DOX with OSMI-1 in HepG2 cells synergistically increased apoptotic cell death through the activation of both the p53 and mitochondrial Bcl2 pathways compared to DOX alone. We also demonstrated that the combination of DOX and OSMI-1 stimulated cell death, dramatically reducing cell proliferation and tumor growth in vivo using a HepG2 xenograft mouse model. These findings indicate that OSMI-1 acts as a potential chemosensitizer by enhancing DOX-induced cell death. This study provides insight into a possible mechanism of chemotherapy resistance, identifies potential novel drug targets, and suggests that OGT inhibition could be utilized in clinical applications to treat hepatocellular carcinoma as well as other cancer types.

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Section: Discussionmentioning

confidence: 99%

O-GlcNAc Transferase Inhibitor Synergistically Enhances Doxorubicin-Induced Apoptosis in HepG2 Cells

Lee

Kwon

2020

Cancers

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“…GRP78 is predominantly located in the ER, and the induction of GRP78 is recognized as a marker of ERS (Lenin et al., 2019). Upregulated GRP78 protein was observed in rat testis after intraperitoneal injection of 10 mg/kg CIS for 5 days (Soni et al., 2016).…”

Section: Discussionmentioning

confidence: 99%

Grape seed proanthocyanidin extract ameliorates cisplatin‐induced testicular apoptosis via PI3K/Akt/mTOR and endoplasmic reticulum stress pathways in rats

et al. 2021

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Testicular toxicity is an adverse reaction of the effective chemotherapy drug cisplatin (CIS). Our previous study found that grape seed proanthocyanidin extract (GSPE) had a protective effect on CIS‐induced testicular toxicity. However, the protective mechanism of GSPE against CIS‐induced testicular toxicity remains unknown. In this study, we aimed to investigate whether GSPE can reduce CIS‐induced testicular toxicity and its potential mechanism in rats. The results showed that GSPE ameliorated CIS‐induced the apoptosis of testicular cells and inhibited the protein levels of Bad, Cyt c, caspase‐9, caspase‐3, caspase‐12, GRP78, CHOP, IRE1α, p‐IRE1α, XBP‐1S, PERK, p‐PERK, eIF2α, and p‐eIF2α. Besides, GSPE reversed the downregulation of PI3K, p‐PI3K, Akt, p‐Akt, mTOR, and p‐mTOR protein expression induced by CIS. These results indicated that GSPE can improve CIS‐induced testicular cells apoptosis via activating PI3K/Akt/mTOR and inhibiting Bad/Cyt c/caspase‐9/caspase‐3 pathways. And GSPE relieved endoplasmic reticulum stress‐mediated apoptosis via inhibiting PREK/eIF2α and IRE1α/XBP‐1S/caspase‐12 pathways. In conclusion, the evidence suggested that GSPE can act as a protective agent against testicular toxicity induced by CIS. Practical applications Testicular toxicity was a well‐known adverse effect of cisplatin (CIS) in cancer treatment. Grape seed proanthocyanidin extract (GSPE) has been reported to serve as one of the most therapeutic potentials agents. In present study, we explored the regulatory effects of GSPE on the apoptosis induced by CIS, which involved testicular apoptosis mechanisms in rats. Our results indicated that CIS caused testicular toxicity via PI3K/AKT/mTOR and ERS mediated apoptosis pathway in rats. This toxicity was attenuated by GSPE treatment via activated PI3K/Akt/mTOR pathway, and inhibiting Bad/CytC/caspase‐9/caspase‐3 as well as PREK/eIF2α, IRE1α/XBP‐1S/caspase‐12 pathways. Our findings suggest that GSPE may be a novel protective agent against testicular toxicity induced by CIS.

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“…Pathway. Like PERK, ATF-6 is an ER transmembrane protein [89]. After dissociation of GRP78, ATF-6 translocates to the Golgi apparatus where it is cleaved and activated by the proteases Sit-1/2.…”

Section: Atf-6mentioning

confidence: 99%

Novel Insight into the Role of Endoplasmic Reticulum Stress in the Pathogenesis of Myocardial Ischemia‐Reperfusion Injury

Zhu

Zhou

2021

Oxidative Medicine and Cellular Longevity

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Impaired function of the endoplasmic reticulum (ER) is followed by evolutionarily conserved cell stress responses, which are employed by cells, including cardiomyocytes, to maintain and/or restore ER homeostasis. ER stress activates the unfolded protein response (UPR) to degrade and remove abnormal proteins from the ER lumen. Although the UPR is an intracellular defense mechanism to sustain cardiomyocyte viability and heart function, excessive activation initiates ER-dependent cardiomyocyte apoptosis. Myocardial ischemia/reperfusion (I/R) injury is a pathological process occurring during or after revascularization of ischemic myocardium. Several molecular mechanisms contribute to the pathogenesis of cardiac I/R injury. Due to the dual protective/degradative effects of ER stress on cardiomyocyte viability and function, it is of interest to understand the basic concepts, regulatory signals, and molecular processes involved in ER stress following myocardial I/R injury. In this review, therefore, we present recent findings related to the novel components of ER stress activation. The complex effects of ER stress and whether they mitigate or exacerbate myocardial I/R injury are summarized to serve as the basis for research into potential therapies for cardioprotection through control of ER homeostasis.

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GRP78 translocation to the cell surface and O-GlcNAcylation of VE-Cadherin contribute to ER stress-mediated endothelial permeability

Cited by 32 publications

References 50 publications

O-GlcNAc Transferase Inhibitor Synergistically Enhances Doxorubicin-Induced Apoptosis in HepG2 Cells

O-GlcNAc Transferase Inhibitor Synergistically Enhances Doxorubicin-Induced Apoptosis in HepG2 Cells

Grape seed proanthocyanidin extract ameliorates cisplatin‐induced testicular apoptosis via PI3K/Akt/mTOR and endoplasmic reticulum stress pathways in rats

Novel Insight into the Role of Endoplasmic Reticulum Stress in the Pathogenesis of Myocardial Ischemia‐Reperfusion Injury

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