Celecoxib enhanced the cytotoxic effect of cisplatin in chemo-resistant gastric cancer xenograft mouse models through a cyclooxygenase-2-dependent manner

The exposure of human endothelial cells to 3-morpholinosydnonimine (SIN-1) induced the expression of cyclooxygenase-2 (COX-2) in a dose- and time-dependent manner. Interestingly, after a prolonged incubation (>8 h) several proteoforms were visualized by Western blot, corresponding to different states of glycosylation of the protein. This effect was specific for SIN-1 that generates peroxynitrite and it was not detected with other nitric oxide-donors. Metabolic labeling experiments using 35S or cycloheximide suggested that the formation of hypoglycosylated COX-2 was dependent on de novo synthesis of the protein rather than the deglycosylation of the native protein. Moreover, SIN-1 reduced the activity of the hexokinase, the enzyme responsible for the first step of glycolysis. The hypoglycosylated COX-2 induced by SIN-1 showed a reduced capacity to generate prostaglandins and the activity was only partially recovered after immunoprecipitation. Finally, hypoglycosylated COX-2 showed a more rapid rate of degradation compared to COX-2 induced by IL-1α and an alteration in the localization with an accumulation mainly detected in the nuclear membrane. Our results have important implication to understand the effect of peroxynitrite on COX-2 expression and activity, and they may help to identify new pharmacological tools direct to increase COX-2 degradation or to inhibit its activity.

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Intracisternal administration of transforming growth factor-β evokes fever through the induction of cyclooxygenase-2 in brain endothelial cells

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00181.2007 ◽

2008 ◽

Vol 294 (1) ◽

pp. R266-R275 ◽

Cited By ~ 3

Author(s):

Shigenobu Matsumura ◽

Tetsuro Shibakusa ◽

Teppei Fujikawa ◽

Hiroyuki Yamada ◽

Kiyoshi Matsumura ◽

...

Keyword(s):

Endothelial Cells ◽

Endothelial Cell ◽

Growth Factor ◽

Proinflammatory Cytokines ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Cyclooxygenase 2 ◽

Dependent Manner ◽

Cox 2 ◽

Β Receptor

Transforming growth factor-β (TGF-β), a pleiotropic cytokine, regulates cell proliferation, differentiation, and apoptosis, and plays a key role in development and tissue homeostasis. TGF-β functions as an anti-inflammatory cytokine because it suppresses microglia and B-lymphocyte functions, as well as the production of proinflammatory cytokines. However, we previously demonstrated that the intracisternal administration of TGF-β induces fever like that produced by proinflammatory cytokines. In this study, we investigated the mechanism of TGF-β-induced fever. The intracisternal administration of TGF-β increased body temperature in a dose-dependent manner. Pretreatment with cyclooxygenase-2 (COX-2)-selective inhibitor significantly suppressed TGF-β-induced fever. COX-2 is known as one of the rate-limiting enzymes of the PGE2 synthesis pathway, suggesting that fever induced by TGF-β is COX-2 and PGE2 dependent. TGF-β increased PGE2 levels in cerebrospinal fluid and increased the expression of COX-2 in the brain. Double immunostaining of COX-2 and von Willebrand factor (vWF, an endothelial cell marker) revealed that COX-2-expressing cells were mainly endothelial cells. Although not all COX-2-immunoreactive cells express TGF-β receptor, some COX-2-immunoreactive cells express activin receptor-like kinase-1 (ALK-1, an endothelial cell-specific TGF-β receptor), suggesting that TGF-β directly or indirectly acts on endothelial cells to induce COX-2 expression. These findings suggest a novel function of TGF-β as a proinflammatory cytokine in the central nervous system.

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2D-DIGE analysis of sera from transgenic mouse models reveals novel candidate protein biomarkers for human gastric cancer

Journal of Proteomics ◽

10.1016/j.jprot.2012.07.002 ◽

2012 ◽

Vol 77 ◽

pp. 40-58 ◽

Cited By ~ 22

Author(s):

Megan A.S. Penno ◽

Manuela Klingler-Hoffmann ◽

Julie A. Brazzatti ◽

Alex Boussioutas ◽

Tracy Putoczki ◽

...

Keyword(s):

Gastric Cancer ◽

Transgenic Mouse ◽

Mouse Models ◽

Human Gastric Cancer ◽

Transgenic Mouse Models ◽

Protein Biomarkers ◽

2D Dige ◽

Candidate Protein ◽

Dige Analysis

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Erk is involved in the differentiation induced by diallyl disulfide in the human gastric cancer cell line MGC803

Cellular & Molecular Biology Letters ◽

10.2478/s11658-006-0034-2 ◽

2006 ◽

Vol 11 (3) ◽

Cited By ~ 21

Author(s):

Hui Ling ◽

Liang-Yun Zhang ◽

Qi Su ◽

Ying Song ◽

Zhao-Yang Luo ◽

...

Keyword(s):

Gastric Cancer ◽

Specific Activity ◽

Lucifer Yellow ◽

Gastric Cancer Cell Line ◽

Major Constituent ◽

Diallyl Disulfide ◽

Human Gastric Cancer ◽

Dependent Manner ◽

Gastric Cancer Cells ◽

Induced Differentiation

AbstractDiallyl disulfide (DADS) is a major constituent of garlic. Previously, we found that DADS both inhibited proliferation in human gastric cancer cells in vitro and in vivo, and induced G2/M arrest. In this study, we investigated whether this differentiation effect was induced by DADS in human gastric cancer MGC803 cells, and whether it was related to an alteration in ERK activity. The results showed that the growth of MGC803 cells was inhibited by DADS. Cells treated with DADS displayed a lower nucleocytoplasmic ratio and tended to form gland and intercellular conjunction structures. The ConA-mediated cell agglutination ratio and cells’ ALP specific activity decreased. In MGC803 cells, dye transfer was limited to a few cells neighbouring the dye-injected cell and to a depth of 1–2 layers beneath the scrape site. However, after treatment with DADS, the LY (Lucifer Yellow) was transferred to several cells immediately neighbouring the microinjected cell and to a depth of 2–4 cell layers from the scrape site. This indicated that DADS induced differentiation in MGC803 cells. Western blot analysis revealed that although DADS did not influence the quantity of ERK1/2 protein expressed, it did decrease its phosphorylation in a concentration-dependent manner, compared with the controls. At 30 mg·L−1, DADS inhibited the activation of ERK1/2 in 15–30 min. These results suggested that the DADS-induced differentiation of MGC803 cells involved an alteration of the ERK1/2 signaling pathway.

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Development of a Novel Orthotopic Gastric Cancer Mouse Model

Biological Procedures Online ◽

10.1186/s12575-020-00137-1 ◽

2021 ◽

Vol 23 (1) ◽

Author(s):

Wonyoung Kang ◽

Leigh Maher ◽

Michael Michaud ◽

Seong-Woo Bae ◽

Seongyeong Kim ◽

...

Keyword(s):

Gastric Cancer ◽

Mouse Models ◽

Cancer Metastasis ◽

Soft Tissues ◽

Tumor Formation ◽

Cancer Model ◽

Orthotopic Model ◽

Cancer Models ◽

Organotropic Metastasis ◽

Nsg Mouse

Abstract Background Gastric cancer metastasis is a highly fatal disease with a five-year survival rate of less than 5%. One major obstacle in studying gastric cancer metastasis is the lack of faithful models available. The cancer xenograft mouse models are widely used to elucidate the mechanisms of cancer development and progression. Current procedures for creating cancer xenografts include both heterotopic (i.e., subcutaneous) and orthotopic transplantation methods. Compared to the heterotopic model, the orthotopic model has been shown to be the more clinically relevant design as it enables the development of cancer metastasis. Although there are several methods in use to develop the orthotopic gastric cancer model, there is not a model which uses various types of tumor materials, such as soft tissues, semi-liquid tissues, or culture derivatives, due to the technical challenges. Thus, developing the applicable orthotopic model which can utilize various tumor materials is essential. Results To overcome the known limitations of the current orthotopic gastric cancer models, such as exposure of tumor fragments to the neighboring organs or only using firm tissues for the orthotopic implantation, we have developed a new method allowing for the complete insertion of soft tissue fragments or homogeneously minced tissues into the stomach submucosa layer of the immunodeficient NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mouse. With this completely-closed transplantation method, tumors with various types of tissue may be used to establish orthotopic gastric cancer models without the risks of exposure to nearby organs or cell leakage. This surgical procedure was highly reproducible in generating forty-eight mouse models with a surgery success rate of 96% and tumor formation of 93%. Among four orthotopic patient-derived xenograft (PDX) models that we generated in this study, we verified that the occurrence of organotropic metastasis in either the liver or peritoneal cavity was the same as that of the donor patients. Conclusion Here we describe a new protocol, step by step, for the establishment of orthotopic xenograft of gastric cancer. This novel technique will be able to increase the use of orthotopic models in broader applications for not only gastric cancer research but also any research related to the stomach microenvironment.

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Repurposing [11C]MC1 for PET Imaging of Cyclooxygenase-2 in Colorectal Cancer Xenograft Mouse Models

Molecular Imaging and Biology ◽

10.1007/s11307-021-01675-0 ◽

2021 ◽

Author(s):

Amanda J. Boyle ◽

Andrea Narvaez ◽

Junchao Tong ◽

Sami S. Zoghbi ◽

Victor W. Pike ◽

...

Keyword(s):

Colorectal Cancer ◽

Mouse Models ◽

Pet Imaging ◽

Cyclooxygenase 2

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