The Role of Cyclooxygenase-2 in Cell Proliferation and Cell Death in Human Malignancies (original) (raw)
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Pathogenic Role of Cyclooxygenase-2 in Cancer
Journal of health science, 2010
Tremendous progress in pathogenic role of cyclooxygenase-2 (COX-2) in diverse cancers triggering the cancer research in the direction of COX-2 inhibitors. Several experimental studies reported overexpression of COX-2 in cancer cells. Mechanisms mediating the pathobiology of COX-2 in cancer are still unclear and needs to be clarified. However, recent studies have shown that the levels of COX-2 isoenzymes are elevated in certain cancers like colo-rectal carcinoma, squamous cell carcinoma of head and neck and certain cancers of lung and breast. Our review article aims to summarize the role of COX-2 in various types of cancer and mechanisms emerged from recent research and their interaction with other cytokines. It seems mechanisms mediating COX-2 and its role in each cancer may be different. In general, possible signaling from the lipids (prostaglandins) can inhibit apoptosis and increase proliferation, motility, and metastatic potential. Furthermore, under certain conditions COX-2 can contribute to angiogenesis. Even, COX-2 is found in lung cancer cells that are responsible for suppressing patients' immune systems and therefore contributing to the growth of lung cancer. COX-2 inhibitors are already in clinical trials for the prevention of colorectal, oral, skin, esophageal and non-small-cell lung cancers and for the treatment of cervical, prostate, and metastatic breast cancers. Heightened role of COX-2 in cancer prompts the pharmaceutical research to design new and safer COX-2 inhibitors to minimize the cardiovascular side effects and improves the treatment of cancer.
Cyclooxygenase‐2 in cancer: A review
Cyclooxygenase‐2 (COX‐2) is frequently expressed in many types of cancers exerting a pleiotropic and multifaceted role in genesis or promotion of carcinogenesis and cancer cell resistance to chemo‐ and radiotherapy. COX‐2 is released by cancer‐associated fibroblasts (CAFs), macrophage type 2 (M2) cells, and cancer cells to the tumor microenvironment (TME). COX‐2 induces cancer stem cell (CSC)‐like activity, and promotes apoptotic resistance, proliferation, angiogenesis, inflammation, invasion, and metastasis of cancer cells. COX‐2 mediated hypoxia within the TME along with its positive interactions with YAP1 and antiapoptotic mediators are all in favor of cancer cell resistance to chemotherapeutic drugs. COX‐2 exerts most of the functions through its metabolite prostaglandin E2. In some and limited situations, COX‐2 may act as an antitumor enzyme. Multiple signals are contributed to the functions of COX‐2 on cancer cells or its regulation. Members of mitogen‐activated protein kinase (MAPK) family, epidermal growth factor receptor (EGFR), and nuclear factor‐κβ are main upstream modulators for COX‐2 in cancer cells. COX‐2 also has interactions with a number of hormones within the body. Inhibition of COX‐2 provides a high possibility to exert therapeutic outcomes in cancer. Administration of COX‐2 inhibitors in a preoperative setting could reduce the risk of metastasis in cancer patients. COX‐2 inhibition also sensitizes cancer cells to treatments like radio‐ and chemotherapy. Chemotherapeutic agents adversely induce COX‐2 activity. Therefore, choosing an appropriate chemotherapy drugs along with adjustment of the type and does for COX‐2 inhibitors based on the type of cancer would be an effective adjuvant strategy for targeting cancer.
International Journal of Cancer, 2001
Elevated prostaglandin E 2 (PGE 2 ) production is a common feature of human malignancies. This activity has often been attributed to increased metabolic activity of the cyclooxygenase enzymes, although a direct comparison of these 2 parameters i.e., prostaglandin production and cox protein expression, is rarely performed in the same malignant tissue. Using a murine model of metastatic breast cancer, we show that PGE 2 levels are positively correlated with increased tumorigenic and metastatic potential. Because prostaglandin synthesis is a product of 2 isoforms of the cyclooxygenase enzyme, we examined the expression and activity of both isoforms. All tumor cell lines examined, regardless of phenotype, express both cox-1 and cox-2 proteins in vitro. In contrast to the uniform cox-2 expression in vitro, only tumors resulting from the transplantation of metastatic cell lines express cox-2 in vivo. Cox-1 is detected in both metastatic and nonmetastatic tumors. Thus, this is the first evidence that, in the tumor milieu, cox-2 expression can be regulated differently in metastatic vs. nonmetastatic lesions. Examination of PGE 2 synthesis in vitro reveals that nearly complete inhibition of prostaglandin synthesis occurs in the presence of either indomethacin, which inhibits both isoforms, or NS398, which is selective for the cox-2 isoform. Thus, even though cell lines express both isoforms, the majority of the prostaglandin synthesis stems from the activity of the inducible, cox-2 isoform. Likewise, cell growth is inhibited by both indomethacin and NS398 in a dose-dependent manner, albeit at higher drug concentrations than required to ablate PGE 2 synthesis. Despite the inhibition of prostaglandin synthesis, the cox-2 enzyme levels (protein and mRNA) were increased by either indomethacin or NS398.
International Journal of Research in Pharmacy and Chemistry Role of CYCLOOXYGENASE-2 in Cancer
Multiple lines of evidence indicate that cyclooxygenase 2 (COX 2) is a bona fide pharmacological target for anticancer therapy. Epidemiological studies show that use of nonsteroidal anti-inflammatory drugs (NSAIDs), which are prototypic inhibitors of COX, are associated with a reduced risk of several malignancies, including colorectal cancer 1. Consistent with this, tumor formation and growth are reduced in animals that are either engineered to be COX 2 deficient or treated with a selective COX 2 inhibitor 2-8. The finding that NSAIDs inhibit COX suggested that prostaglandins, the products of COX activity, substantially contribute to carcinogenesis. For example, COX-derived prostaglandins have been implicated in angiogenesis 9. 10. The recent development of selective inhibitors of the inducible form of COX, COX 2, represents another important advance. Importantly, selective COX 2 inhibitors cause fewer serious
Prostaglandins, Leukotrienes and Essential Fatty Acids, 2002
Increased prostaglandins (PGs) are associated with many inflammatory pathophysiological conditions; and are synthesized from arachidonic acid by either of 2 enzymes, cyclooxygenase-1 (COX-1) or -2 (COX-2). Recent epidemiologic, expression, and pharmacologic studies suggest COX-2 derived metabolites also playa functionalrole in the maintenance of tumor viability, growth and metastasis. Archival and/or prospectively collected human tissues were prepared for immunohistochemistry, and representative cases assayed viaWestern blot, RT-PCR, orTAQman analysis. Consistent overexpression of COX-2 was observed in a broad range of premalignant, malignant, and metastatic human epithelial cancers. COX-2 was detected in ca. 85% of the hyperproliferating, dysplastic, and neoplastic epithelial cells, and in the existing and angiogenic vasculature within and adjacent to hyperplastic/neoplastic lesions.These data collectively imply COX-2 may play an important role during premalignant hyperproliferation, as well as the later stages of invasive carcinoma and metastasis in various human epithelial cancers. &
Cancer research, 2000
The up-regulation of cyclooxygenase 2 (COX-2) expression is a frequent occurrence in a variety of different tumors. In this study, COX-2 protein expression was investigated in 50 glioma and 3 normal brain specimens by immunohistochemistry. Expression of COX-2 protein was observed in all normal brain and glioma specimens by immunohistochemistry, regardless of histological grade. The immunoreactive score was significantly higher in high-grade glioma than low-grade glioma and normal brain specimens. For a subset of these tumors (nine gliomas and three normal brain), Western blot analysis was also performed. COX-2 protein was detected in all specimens by Western blot analysis. The effect of the specific COX-2 inhibitor NS-398 on monolayer cell cultures and three-dimensional glioma spheroids was investigated using U-87MG and U-251MG human glioblastoma cell lines. The proliferation rate was assessed in monolayer cultures. In addition, a growth assay, a migration assay, an apoptosis assay,...
Cyclooxygenase-2 modulates cellular growth and promotes tumorigenesis
Journal of Cellular and Molecular Medicine, 2003
Cyclooxygenase (COX) -2 and the prostaglandins resulting from its enzymatic activity have been shown to play a role in modulating cell growth and development of human neoplasia. Evidence includes a direct relationship between COX-2 expression and cancer incidence in humans and animal models, increased tumorigenesis after genetic manipulation of COX-2, and significant anti-tumor properties of non-steroidal anti-inflammatory drugs in animal models and in some human cancers. Recent data showed that COX-2 and the derived prostaglandins are involved in control of cellular growth, apoptosis, and signal through a group of nuclear receptors named peroxisome proliferator-activated receptors (PPARs). In this article we will review some of the findings suggesting that COX-2 is involved in multiple cellular mechanisms that lead to tumorigenesis.
Pharmaceuticals, 2018
Prostaglandins and thromboxane are lipid signaling molecules deriving from arachidonic acid by the action of the cyclooxygenase isoenzymes COX-1 and COX-2. The role of cyclooxygenases (particularly COX-2) and prostaglandins (particularly PGE2) in cancer-related inflammation has been extensively investigated. In contrast, COX-1 has received less attention, although its expression increases in several human cancers and a pathogenetic role emerges from experimental models. COX-1 and COX-2 isoforms seem to operate in a coordinate manner in cancer pathophysiology, especially in the tumorigenesis process. However, in some cases, exemplified by the serous ovarian carcinoma, COX-1 plays a pivotal role, suggesting that other histopathological and molecular subtypes of cancer disease could share this feature. Importantly, the analysis of functional implications of COX-1-signaling, as well as of pharmacological action of COX-1-selective inhibitors, should not be restricted to the COX pathway a...
Cyclooxygenases in cancer: progress and perspective
Cancer Letters, 2004
Aspirin has been used to control pain and inflammation for over a century. Epidemiological studies first associated a decreased incidence of colorectal cancer with the long-term use of aspirin in the early 1980s. Near the same time the first reports showing regression of colorectal adenomas in response to the non-steroidal anti-inflammatory drug (NSAID) sulindac were reported. In subsequent years, the use of other NSAIDs, which inhibit cyclooxygenase (COX) enzymes, was linked to reduced cancer risk in multiple tissues including those of the breast, prostate, and lung. Together these studies resulted in the identification of a new cancer preventive and/or therapeutic target-COX enzymes, especially COX-2. Meanwhile, the overexpression of COX-2, and less consistently, the upstream and downstream enzymes of the prostaglandin synthesis pathway, was demonstrated in multiple cancer types and some pre-neoplastic lesions. Direct interactions of prostaglandins with their receptors through autocrine or paracrine pathways to enhance cellular survival or stimulate angiogenesis have been proposed as the molecular mechanisms underlying the pro-carcinogenic functions of COX-2. The rapid development of safe and effective inhibitors targeting individual COX enzymes not only dramatically improved our understanding of the function of COX-2, but also resulted in discovery of COX independent functions of NSAIDs, providing important hints for future drug design. Here we review the fundamental features of COX enzymes, especially as related to carcinogenesis, their expression and function in both animal tumor models and clinical cancers and the proposed mechanisms behind their roles in cancer. q (A.M. De Marzo).