COX-2 and Gastric Cancer: More on Inflammation and Neoplasia

The c-Myc promoter binding protein 1 (MBP-1) is a transcriptional suppressor of c-myc expression and involved in control of tumorigenesis. Gastric cancer is one of the most frequent neoplasms and lethal malignancies worldwide. So far, the regulatory mechanism of its aggressiveness has not been clearly characterized. Here we studied roles of MBP-1 in gastric cancer progression. We found that cell proliferation was inhibited by MBP-1 overexpression in human stomach adenocarcinoma SC-M1 cells. Colony formation, migration, and invasion abilities of SC-M1 cells were suppressed by MBP-1 overexpression but promoted by MBP-1 knockdown. Furthermore, the xenografted tumor growth of SC-M1 cells was suppressed by MBP-1 overexpression. Metastasis in lungs of mice was inhibited by MBP-1 after tail vein injection with SC-M1 cells. MBP-1 also suppressed epithelial-mesenchymal transition in SC-M1 cells. Additionally, MBP-1 bound on cyclooxygenase 2 (COX-2) promoter and downregulated COX-2 expression. The MBP-1-suppressed tumor progression in SC-M1 cells were through inhibition of COX-2 expression. MBP-1 also exerted a suppressive effect on tumor progression of other gastric cancer cells such as AGS and NUGC-3 cells. Taken together, these results suggest that MBP-1–suppressed COX-2 expression plays an important role in the inhibition of growth and progression of gastric cancer.

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Cyclooxygenase-2 inhibitors suppress the growth of gastric cancer xenografts via induction of apoptosis in nude mice

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1998.274.6.g1061 ◽

1998 ◽

Vol 274 (6) ◽

pp. G1061-G1067 ◽

Cited By ~ 21

Author(s):

Hitoshi Sawaoka ◽

Sunao Kawano ◽

Shingo Tsuji ◽

Masahiko Tsujii ◽

Edhi S. Gunawan ◽

...

Keyword(s):

Gastric Cancer ◽

Cancer Cells ◽

Nude Mice ◽

Tumor Volume ◽

Malignant Tumors ◽

Apoptotic Cell ◽

Dependent Manner ◽

Cox 2 ◽

Induced Apoptosis ◽

Cox 2 Inhibitors

To clarify the role of mitogen-inducible cyclooxygenase (COX-2) in the development of malignant tumors, we investigated the effects of COX-2 inhibitors on the growth of gastric cancer xenografts in nude mice in vivo. MKN45 gastric cancer cells (5 × 106cells/animal) that overexpress COX-2 were inoculated subcutaneously into athymic mice. NS-398, a specific COX-2 inhibitor, or indomethacin, a nonspecific COX-2 inhibitor, was administered orally to animals every day for 20 days. These drugs reduced the tumor volume significantly. Immunohistochemistry using bromodeoxyuridine, nick end labeling, and electron microscopy showed that NS-398 induced apoptosis in cancer cells in a dose-dependent manner and inhibited cancer cell replication slightly. Indomethacin also induced apoptosis and suppressed replication of tumor cells. There was a significant negative correlation between tumor volume and apoptotic cell number within the tumor. These results are consistent with the hypothesis that COX-2 inhibitors suppress growth of gastric cancer xenografts mainly by inducing apoptosis and suppressing replication of the neoplastic cells. It follows that COX-2 plays an important role in the development of gastric cancer.

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Targeted inhibition of COX-2 expression by RNA interference suppresses tumor growth and potentiates chemosensitivity to cisplatin in human gastric cancer cells

Oncology Reports ◽

10.3892/or.18.6.1557 ◽

2007 ◽

Cited By ~ 3

Author(s):

Michael Chan ◽

Christine Wong ◽

Alfred Cheng ◽

Victor Chan ◽

Ka Chan ◽

...

Keyword(s):

Gastric Cancer ◽

Rna Interference ◽

Tumor Growth ◽

Cancer Cells ◽

Human Gastric Cancer ◽

Gastric Cancer Cells ◽

Cox 2 ◽

Targeted Inhibition

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Lycopene Inhibits Activation of Epidermal Growth Factor Receptor and Expression of Cyclooxygenase-2 in Gastric Cancer Cells

Nutrients ◽

10.3390/nu11092113 ◽

2019 ◽

Vol 11 (9) ◽

pp. 2113 ◽

Cited By ~ 3

Author(s):

Hwana Han ◽

Joo Weon Lim ◽

Hyeyoung Kim

Keyword(s):

Gene Expression ◽

Gastric Cancer ◽

Epidermal Growth Factor Receptor ◽

Growth Factor ◽

Epidermal Growth Factor ◽

Cancer Cells ◽

Growth Factor Receptor ◽

Ags Cells ◽

Epidermal Growth ◽

Cox 2

Reactive oxygen species (ROS) contribute to the oncogenic phenotype of cancer cells by acting as signaling molecules for inducing proliferation. ROS are known to activate the epidermal growth factor receptor (EGFR), which causes the activation of the Ras/mitogen-activated protein kinases (MAPKs) pathway. The Ras-dependent pathway promotes the activation of nuclear factor-kappa-light-chain-enhancer of activated B cells (NF-κB), a transcriptional modulator of cyclooxygenase-2 (COX-2) that induces cell proliferation. Lycopene is a potent antioxidant carotenoid and is responsible for the red color of fruits and vegetables. This study aims to investigate whether lycopene inhibits proliferation and induces apoptosis in gastric cancer AGS cells by suppressing the EGFR/Ras/MAPK and NF-κB-COX-2 signaling axis. Lycopene decreased cell viability and increased apoptotic indices (DNA fragmentation, apoptosis inducing factor, cleavage of caspase-3 and caspase-9, Bax/Bcl-2 ratio). Lycopene reduced the level of intracellular and mitochondrial ROS and decreased the activation of the ROS-mediated EGFR/Ras/extracellular signal-regulated kinase (ERK) and p38 MAPK pathways, thus leading to attenuation of the DNA-binding activity of NF-κB p50/p50 and the level of COX-2 gene expression. These results show that lycopene-induced apoptosis and inhibition of proliferation occur via inhibition of ROS-activated EGFR/Ras/ERK and p38 MAPK pathways and NF-κB-mediated COX-2 gene expression in AGS cells. In conclusion, consumption of lycopene-enriched foods could decrease the incidence of gastric cancer.

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Elevated expression of Foxp3 in tumor-infiltrating Treg cells suppresses T-cell proliferation and contributes to gastric cancer progression in a COX-2-dependent manner

Clinical Immunology ◽

10.1016/j.clim.2009.10.005 ◽

2010 ◽

Vol 134 (3) ◽

pp. 277-288 ◽

Cited By ~ 84

Author(s):

Xiang-Liang Yuan ◽

Lei Chen ◽

Mei-Xing Li ◽

Ping Dong ◽

Jian Xue ◽

...

Keyword(s):

Gastric Cancer ◽

Cell Proliferation ◽

T Cell ◽

Cancer Progression ◽

Treg Cells ◽

T Cell Proliferation ◽

Dependent Manner ◽

Elevated Expression ◽

Cox 2 ◽

Gastric Cancer Progression

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COX-2 Inhibitors and Gastric Cancer

Gastroenterology Research and Practice ◽

10.1155/2014/132320 ◽

2014 ◽

Vol 2014 ◽

pp. 1-7 ◽

Cited By ~ 12

Author(s):

Zhen Wang ◽

Jun-qiang Chen ◽

Jin-lu Liu

Keyword(s):

Gastric Cancer ◽

Antitumor Agents ◽

Prostaglandin E ◽

Potential Toxicity ◽

Chemopreventive Agents ◽

Treatment Regimens ◽

Cox 2 ◽

Cox 2 Inhibitors ◽

Cancer Studies ◽

Selection Of

The evidence that cyclooxygenase-2 (COX-2) is upregulated and plays an important role in carcinogenesis of gastric cancer has triggered the topic of COX-2 inhibitors as chemopreventive agents for gastric cancer. Studies find that COX-2 inhibitors are associated not only with chemoprophylactic effects, but also with chemotherapeutic potentials in gastric cancer. Both COX-dependent and COX-independent pathways have a role in the anticancer efficiency of COX-2 inhibitors. However, enthusiasm is thwarted by the potential toxicity, that is, gastrointestinal toxicity of nonselective COX-2 inhibitors and cardiovascular risk of selective COX-2 inhibitors. Therefore, more studies are needed to develop new targeted antitumor agents (such as prostaglandin E receptor antagonist) and to define fundamental questions such as optimal treatment regimens, integration of cotherapy, and careful selection of candidates.

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