Increased cyclooxygenase-2 (COX-2): a potential role in the pathogenesis of lymphoma
Introduction
More than 20 years ago high concentrations of prostaglandins were found in human and animal tumor tissues. This relationship of increased levels of prostaglandins stimulated much research examining their role in carcinogenesis. There are several lines of evidence that support the role of prostaglandins in carcinomatosis. These include in vitro data, pre-clinical rodent models, human clinical trials, and epidemiological studies [1].
The enzyme involved in the first step of prostaglandin synthesis from arachidonic acid is designated as cyclooxygenase (COX), prostaglandin H synthase, or prostaglandin-endoperoxide synthase [2]. Two isoenzymes exist in the mammalian body, constitutive COX-1, and inducible COX-2. While COX-1 is involved in homeostasis of various physiologic functions, COX-2 is responsible for many inflammatory processes and organ development. COX-2 synthesizes many significant prostaglandins, for example, prostaglandin E2 (PGE2). PGE2 has a multitude of physiologic effects including, mediating pain, modulation of lymphocyte cytokine production, and induction of IL-6 and haptoglobin, both of which are important regulators of angiogenisis [3]. After the discovery of COX-2 in the early 1990s, many of the inhibitory effects of non-steroidal anti-inflammatory drugs (NSAIDs) on human colon cancer were ascribed to these drug’s effects on COX-2. COX-2 is dramatically up regulated during pathologic conditions, such as inflammation and cancer. The COX-2 gene, an immediate-early response gene, is rapidly induced in response to mitogenic or inflammatory stimuli including: tumor promoters, cytokines, endotoxin, and growth factors [4].
Moreover, COX-2 expression is regulated by oncogenes and p53 in a positive and negative manner, respectively. The involvement of p53 in the regulation of COX-2 expression may explain why COX-2 expression is up regulated in various forms of cancer that contain the mutant p53 [5], [6], [7], [8], [9], [10]. The premise that COX-2 is involved in that pathologic processes of cancer growth and progression is further supported by animal studies showing that tumorogenisis is inhibited in COX-2 knockout mice [11], [12]. Evidence suggests that the increase in tumorigenic potential by COX-2 overexpression is associated with resistance to apoptosis [13]. Selective inhibitors of COX-2 have been demonstrated to induce apoptosis in a variety of cancer cells, including those of colon [14], [15], [16], stomach [17], prostate [18], and breast. The biochemical mechanism underlying COX-2 inhibitor-induced apoptosis, however, remains elusive. Based on recent studies several mechanisms have been proposed by which COX-2 over-expression inhibits apoptosis, including decreased ceramide production (a known death signal) [19], increased anti-apoptotic Bcl-2 expression [20], and up-regulation of the anti-apoptotic kinase Akt [21]. Moreover, it appears that there is correlation with the amount of COX-2 and the tumor size and the propensity to invade underlying tissue, the latter is proposed to be secondary to the angiogenic properties of COX-2 [3].
The lymphomas are a diverse group of clinicopathologic entities that are the result of malignant transformation of lymphocytes and are the sixth most common cause of cancer-related deaths in the United States [22], [23]. As with other malignancies, the accumulation of genetic abnormalities are required for malignant transformation of human lymphocytes [24], [25]. Involved genes include those important in apoptosis, proliferation, cell adhesion, and inflammation. During an inflammatory reaction, immune and accessory cells are stimulated to secrete PGE2 in response to agents, such as IL-1, LPS, or antigen antibody complexes. PGE2 has been found to be a potent regulator of B lymphocyte function [26]. The effects on B lymphocytes continue to be defined, however, they likely include inhibitory and stimulatory roles that include inhibition of early activation events, potentiation of immunoglobulin production and isotype class switching. The role of prostaglandins in lymphoid carcinogenesis is also poorly defined, however, there is evidence that PGE2 differentially regulates murine B cell lymphoma growth. In addition, high levels of PGE have been found in patients with lymphoma [27]. Recent studies have revealed that in patients with chronic lymphocytic leukemia COX-2 expression and activity, in the form of PGE2 production, could be induced with LPS, anti-IgM or CD40 [28]. In addition, treatment of mice with indomethacin lead to near complete inhibition of plasmacytoma development in mice injected with pristine [29], [30].
Based on the paucity of data in human lymphomas, and the probable important role of COX-2 in the pathogenesis of many human malignancies we sought to examine the role of COX-2 in the pathogenesis of human B cell lymphomas.
Section snippets
Reagents
Celecoxib (CEL) was a kind gift of Pfizer Pharmaceuticals, and resuspended in dimethyl sulfoxide (DMSO), with a final concentration of DMSO after incubation not to exceed 1.8%. Chlorambucil (CHL) was purchased from Sigma (St. Louis, MO) and resuspended in ethanol, with a final concentration of ethanol after incubation not to exceed 0.5%. All incubations, including non-drug-containing controls were carried out with the same final concentration of DMSO or ethanol. The rabbit anti-Bcl-2, Bcl-xL,
COX-2 expression is increased in B cell lymphoma cell lines
Cox-2 expression is usually absent or present at low levels in normal tissues. Cox-2 is induced by cytokines and growth factors, and has been found to be constitutively expressed in several forms of human cancer. The expression level of COX-2 was examined in six B cell Burkitts Lymphoma cell lines by immunoblot analysis. Constitutive expression was detected in all the lines examined, and when compared to normal peripheral blood B cells there was an approximately 2.2–4.3-fold increase in COX-2
Discussion
This study reveals that, as for a number of other malignancies, when compared to its benign counterpart, COX-2 expression is consistently increased in a panel B cell lymphoma cell lines. Furthermore, when compared to resting and activated primary B cells, we found an increase in the tyrosine phosphorylated form of COX-2. Previous studies have correlated COX-2 tyrosine phosphorylation with COX-2 enzyme activity. Incubation of lymphoma cell lines overexpressing COX-2 with the selective COX-2
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