Increased Endoplasmic Reticulum Stress Response Is Involved in Clopidogrel-Induced Apoptosis of Gastric Epithelial Cells

Wu, Hao; Duan, Zhaotao; Jiang, Ziyan; Cao, Weijun; Wang, Zhibing; Hu, Kewei; Gao, Xin; Wang, Shukui; He, Bangshun; Zhang, Zhenyu; Xie, Hong‐Guang

doi:10.1371/journal.pone.0074381

Cited by 13 publications

(12 citation statements)

References 56 publications

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“…A possible explanation is that ticagrelor activates the mitogen-activated protein kinase (MAPK) pathway. Studies on gastric epithelial cells have shown that clopidogrel—another P2Y12 antagonist—induces ER stress through activation of p38-MAPK [ 39 ]. In addition, the P2Y12 receptor has been shown to act on the MAPK pathway in microglial cells during nerve injury [ 40 ].…”

Section: Discussionmentioning

confidence: 99%

Inhibiting P2Y12 in Macrophages Induces Endoplasmic Reticulum Stress and Promotes an Anti-Tumoral Phenotype

Pavlović

Kopsida

Gerwins

et al. 2020

IJMS

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The P2Y12 receptor is an adenosine diphosphate responsive G protein-coupled receptor expressed on the surface of platelets and is the pharmacologic target of several anti-thrombotic agents. In this study, we use liver samples from mice with cirrhosis and hepatocellular carcinoma to show that P2Y12 is expressed by macrophages in the liver. Using in vitro methods, we show that inhibition of P2Y12 with ticagrelor enhances tumor cell phagocytosis by macrophages and induces an anti-tumoral phenotype. Treatment with ticagrelor also increases the expression of several actors of the endoplasmic reticulum (ER) stress pathways, suggesting activation of the unfolded protein response (UPR). Inhibiting the UPR with tauroursodeoxycholic acid (Tudca) diminishes the pro-phagocytotic effect of ticagrelor, thereby indicating that P2Y12 mediates macrophage function through activation of ER stress pathways. This could be relevant in the pathogenesis of chronic liver disease and cancer, as macrophages are considered key players in these inflammation-driven pathologies.

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Section: Discussionmentioning

confidence: 99%

Inhibiting P2Y12 in Macrophages Induces Endoplasmic Reticulum Stress and Promotes an Anti-Tumoral Phenotype

Pavlović

Kopsida

Gerwins

et al. 2020

IJMS

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“…When a large number of unfolded or misfolded proteins accumulate in the endoplasmic reticulum, the normal physiological function will be changed. This phenomenon is known as ERS 36,37 . ERS primarily acts through activating IRE-1, which is a significant event in andrographolide-induced CRC cell death 38 .…”

Section: Discussionmentioning

confidence: 99%

MiR-451a suppressing BAP31 can inhibit proliferation and increase apoptosis through inducing ER stress in colorectal cancer

Han

Bai

et al. 2019

Cell Death Dis

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The global morbidity and mortality of colorectal cancer (CRC) are ranked the third among gastrointestinal tumors in the world. MiR-451a is associated with several types of cancer, including CRC. However, the roles and mechanisms of miR-451a in CRC have not been elucidated. BAP31 is a predicted target gene of miR-451a in our suppression subtractive hybridization library. Its relationship with miR-451a and function in CRC are unclear. We hypothesized that miR-451a could induce apoptosis through suppressing BAP31 in CRC. Immunohistochemistry and real-time PCR were used to measure BAP31 expressions in CRC tissues and pericarcinous tissues from 57 CRC patients and CRC cell lines. Dual-luciferase reporter assay was used to detect the binding of miR-451a to BAP31. The expression of BAP31 protein in CRC tissues was significantly higher than that in pericarcinous tissues, which was correlated with distant metastasis and advanced clinical stages of CRC patients. The expression of BAP31 was higher in HCT116, HT29, SW620, and DLD cells than that in the normal colonic epithelial cell line NCM460. The expression of BAP31 was absolutely down-regulated when over-expressing miR-451a in HCT116 and SW620 cells compared with control cells. Mir-451a inhibited the expression of BAP31 by binding to its 5’-UTR. Over-expressing miR-451a or silencing BAP31 suppressed the proliferation and apoptosis of CRC cells by increasing the expressions of endoplasmic reticulum stress (ERS)-associated proteins, including GRP78/BIP, BAX, and PERK/elF2α/ATF4/CHOP, which resulted in increased ERS, cytoplasmic calcium ion flowing, and apoptosis of CRC cells. These changes resulting from over-expressing miR-451a were reversed by over-expressing BAP31 with mutated miR-451a-binding sites. Over-expressing miR-451a or silencing BAP31 inhibited tumor growth by inducing ERS. The present study demonstrated that miR-451a can inhibit proliferation and increase apoptosis through inducing ERS by binding to the 5’-UTR of BAP31 in CRC.

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“…The human embryonic kidney cell line HEK293 was purchased from the Microbix Biosystems (Ontario, Canada). The human gastric mucosa epithelial cell line GES-1 was kindly gifted by the Nanjing First Hospital, Nanjing Medical University (Nanjing, China) [30, 31]. The cells were cultured at 37°C and 5% CO 2 in Dulbecco's modified Eagle's medium (DMEM) with 10% fetal bovine serum (FBS), 10 U/mL penicillin and 10 U/mL streptomycin.…”

Section: Methodsmentioning

confidence: 99%

Survivin promoter-regulated oncolytic adenovirus with Hsp70 gene exerts effective antitumor efficacy in gastric cancer immunotherapy

Wang

et al. 2013

Oncotarget

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Gene therapy is a promising adjuvant therapeutic strategy for cancer treatment. To overcome the limitations of current gene therapy, such as poor transfection efficiency of vectors, low levels of transgene expression and lack of tumor targeting, the Survivin promoter was used to regulate the selective replication of oncolytic adenovirus in tumor cells, and the heat shock protein 70 (Hsp70) gene was loaded as the anticancer transgene to generate an AdSurp-Hsp70 viral therapy system. The efficacy of this targeted immunotherapy was examined in gastric cancer. The experiments showed that the oncolytic adenovirus can selectively replicate in and lyse the Survivin-positive gastric cancer cells, without significant toxicity to normal cells. AdSurp-Hsp70 reduced viability of cancer cells and inhibited tumor growth of gastric cancer xenografts in immuno-deficient and immuno-reconstruction mouse models. AdSurp-Hsp70 produced dual antitumor effects due to viral replication and high Hsp70 expression. This therapeutic system used the Survivin promoter-regulated oncolytic adenovirus vector to mediate targeted expression of the Hsp70 gene and ensure safety and efficacy for subsequent gene therapy programs against a variety of cancers.

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Increased Endoplasmic Reticulum Stress Response Is Involved in Clopidogrel-Induced Apoptosis of Gastric Epithelial Cells

Cited by 13 publications

References 56 publications

Inhibiting P2Y12 in Macrophages Induces Endoplasmic Reticulum Stress and Promotes an Anti-Tumoral Phenotype

Inhibiting P2Y12 in Macrophages Induces Endoplasmic Reticulum Stress and Promotes an Anti-Tumoral Phenotype

MiR-451a suppressing BAP31 can inhibit proliferation and increase apoptosis through inducing ER stress in colorectal cancer

Survivin promoter-regulated oncolytic adenovirus with Hsp70 gene exerts effective antitumor efficacy in gastric cancer immunotherapy

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