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Mounting evidence from preclinical and clinical studies suggests that persistent inflammation functions as a driving force in the journey to cancer. Cyclooxygenase-2 (COX-2) is a key enzyme involved in inflammatory signaling. While being transiently upregulated upon inflammatory stimuli, COX-2 has been found to be consistently overexpressed in human colorectal cancer and several other malignancies. The association between chronic inflammation and cancer has been revisited: cancer can arise when inflammation fails to resolve. Besides its proinflammatory functions, COX-2 also catalyzes the production of pro-resolving as well as anti-inflammatory metabolites from polyunsaturated fatty acids. This may account for the side effects caused by long term use of some COX-2 inhibitory drugs during the cancer chemopreventive trials. This review summarizes the latest findings highlighting the dual functions of COX-2 in the context of its implications in the development, maintenance, and progression of cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

There is a plethora of evidence to support that inflammation is causally linked to carcinogenesis. Cyclooxygenase-2 (COX-2), a rate-limiting enzyme in the biosynthesis of prostaglandins, is inappropriately overexpressed in various cancers and hence recognized as one of the hallmarks of chronic inflammation-associated malignancies. However, the mechanistic role of COX-2 as a link between inflammation and cancer remains largely undefined. In this study, we found that 15-deoxy-Δ 12,14 -prostaglandin J 2 (15d-PGJ 2 ), one of the final products of COX-2, induced upregulation of vascular endothelial growth factor (VEGF) and capillary formation and migration through nuclear factor erythroid 2-related factor 2 (NRF2)-dependent heme oxygenase-1 (HO-1) induction in MCF-7 cells. Analysis of the publicly available TCGA data set showed that high mRNA levels of both COX-2 and NRF2 correlated with the poor clinical outcomes in breast cancer patients. Moreover, human tissue analysis showed that the levels of 15d-PGJ 2 as well the expression of COX-2, NRF2, and HO-1 were found to be increased in human breast cancer tissues. In conclusion, the elevated levels of 15d-PGJ 2 during inflammatory response activate VEGF expression through NRF2-driven induction of HO-1 in human breast cancer cells, proposing a novel mechanism underlying the oncogenic function of 15d-PGJ 2 .

Multiple lines of compelling evidence from clinical and population-based studies support that hyperinsulinemia often accompanying obesity-associated insulin insensitivity promotes colon carcinogenesis. Insulin can acetylate, thereby activating sterol regulator element-binding protein 1 (SREBP-1), a prime transcription factor responsible for expression of genes involved in lipogenesis. Moreover, SREBP-1 upregulates cyclooxygenase-2 (COX-2), a key player in inflammatory signaling. Docosahexaenoic acid (DHA), a representative omega-3 polyunsaturated fatty acid, has been known to negatively regulate SREBP-1, but the underlying molecular mechanism is not fully clarified yet. This prompted us to investigate whether DHA could inhibit insulin-induced activation of SREBP-1 and COX-2 expression in the context of its potential protective effect on obesity-induced inflammation and carcinogenesis. SIRT1, a NAD(+)-dependent histone/non-histone protein deacetylase, has been reported to inhibit intracellular signaling mediated by SREBP-1 through deacetylation of this transcription factor. We found that DHA induced SIRT1 expression in CCD841CoN human colon epithelial cells. DHA abrogated insulin-induced acetylation as well as expression of SREBP-1 and COX-2 upregulation. Insulin-induced stimulation of CCD841CoN cell migration was also inhibited by DHA. These effects mediated by DHA were attenuated by pharmacologic inhibition of SIRT1. Hyperinsulinemia or insulin resistance is considered to be associated with obesity-associated inflammation. Genetically obese (ob/ob) mice showed higher colonic expression levels of both SREBP-1 and COX-2 than did normal lean mice. Likewise, expression of SREBP-1 and COX-2 was elevated in human colon tumor specimens compared with surrounding normal tissues. In conclusion, DHA may protect against obesity-associated inflammation and colon carcinogenesis by suppressing insulin-induced activation of SREBP-1 and expression of COX-2 through up-regulation of SIRT1., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Exposure to ultraviolet B (UVB) radiation, a complete environmental carcinogen, induces oxidative and inflammatory skin damage, thereby increasing the risk of skin carcinogenesis. The antioxidant and anti-inflammatory activities of a wide variety of plant polyphenols have been reported. Rutin (3-rhamnosyl-glucosylquercetin), a polyphenol present in many edible plants, possesses diverse pharmacological properties including antioxidant, anti-inflammatory, antimutagenic and anticancer activities. The present study was aimed to investigate the effects of rutin on UVB-induced inflammation in mouse skin in vivo. Topical application of rutin onto the dorsal skin of female HR-1 hairless mice 30 min prior to UVB irradiation diminished epidermal hyperplasia and the levels of proteins modified by 4-hydroxynonenal, which is a biochemical hallmark of lipid peroxidation. Topical application of rutin also significantly inhibited UVB-induced expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS), two representative inflammatory enzymes, in hairless mouse skin. Rutin inhibited the DNA binding of activator protein-1 (AP-1) and phosphorylation of signal transducer and activator of transcription-3 (STAT3) in mouse skin exposed to UVB. Moreover, rutin attenuated UVB-induced phosphorylation of p38 mitogen-activated protein (MAP) kinase and c-Jun-N-terminal kinase (JNK). Pharmacological inhibition of p38 MAP kinase and JNK decreased UVB-induced expression of COX-2 in mouse skin. Taken together, these findings suggest that rutin exerts anti-inflammatory effects in UVB-irradiated mouse skin by inhibiting expression of COX-2 and iNOS, which is attributable to its suppression of p38 MAP kinase and JNK signaling responsible for AP-1 activation., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Genistein, an isoflavone present in soy products, has chemopreventive effects on mammary carcinogenesis. In the present study, we have investigated the effects of genistein on phorbol ester-induced expression of cyclooxygenase-2 (COX-2) that plays an important role in the pathophysiology of inflammation-associated carcinogenesis. Pretreatment of cultured human breast epithelial (MCF10A) cells with genistein reduced COX-2 expression induced by 12-O-tetradecanoylphorbol-13-acetate (TPA). There are multiple lines of evidence supporting that the induction of COX-2 is regulated by the eukaryotic transcription factor NF-κB. Genistein failed to inhibit TPA-induced nuclear translocation and DNA binding of NF-κB as well as degradation of IκB. However, genistein abrogated the TPA-induced transcriptional activity of NF-κB as determined by the luciferase reporter gene assay. Genistein inhibited phosphorylation of the p65 subunit of NF-κB and its interaction with cAMP regulatory element-binding protein-binding protein (CBP)/p300 and TATA-binding protein (TBP). TPA-induced NF-κB phosphorylation was abolished by pharmacological inhibition of extracellular signal-regulated kinase (ERK). Likewise, pharmacologic inhibition or dominant negative mutation of ERK suppressed phosphorylation of p65. The above findings, taken together, suggest that genistein inhibits TPA-induced COX-2 expression in MCF10A cells by blocking ERK-mediated phosphorylation of p65 and its subsequent interaction with CBP and TBP., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Sulforaphane, an isothiocyanate present in cruciferous vegetables, has been reported to possess anti-inflammatory and cancer chemopreventive properties. However, the molecular mechanisms by which sulforaphane suppresses inflammation and carcinogenesis are yet to be fully elucidated. Since the aberrant expression of cyclooxygenase-2 (COX-2) links inflammation and cancer, the present study was aimed to elucidate the mechanisms by which sulforaphane modulates COX-2 overexpression in human mammary epithelial (MCF-10A) cells stimulated with a prototypic tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). Treatment of MCF-10A cells with sulforaphane significantly inhibited TPA-induced expression of COX-2 protein and its mRNA transcript. Transient transfection of cells with deletion mutant constructs of COX-2 promoter revealed that the transcription factor nuclear factor-kappaB (NF-κB) plays a key role in TPA-induced COX-2 expression in MCF-10A cells. Pretreatment with sulforaphane significantly attenuated nuclear localization, DNA binding and the transcriptional activity of NF-κB through inhibition of phosphorylation and subsequent degradation of IκBα in MCF-10A cells stimulated with TPA. Sulforaphane also attenuated TPA-induced activation of IκB kinases (IKK), NF-κB-activating kinase (NAK) and extracellular signal-regulated kinase-1/2 (ERK1/2). Pharmacological inhibition of IKK or transient transfection of cells with dominant-negative mutant forms of this kinase abrogated TPA-induced NF-κB activation and COX-2 expression. In addition, the blockade of ERK1/2 activation negated the catalytic activity of IKKα, but not that of IKKβ, whereas silencing NAK by specific siRNA abrogated the IKKβ activity in TPA-treated cells. Taken together, sulforaphane inhibits TPA-induced NF-κB activation and COX-2 expression in MCF-10A cells by blocking two distinct signaling pathways mediated by ERK1/2-IKKα and NAK-IKKβ., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Exposure to ultraviolet-B (UVB) radiation induces inflammation and photocarcinogenesis in mammalian skin. Docosahexaenoic acid (DHA), a representative ω-3 polyunsaturated fatty acid, has been reported to possess anti-inflammatory and chemopreventive properties. In the present study, we investigated the molecular mechanisms underlying the inhibitory effects of DHA on UVB-induced inflammation in mouse skin. Our study revealed that topical application of DHA prior to UVB irradiation attenuated the expression of cyclooxygenase-2 (COX-2) and NAD(P)H:oxidase-4 (NOX-4) in hairless mouse skin. DHA pretreatment also attenuated UVB-induced DNA binding of nuclear factor-kappaB (NF-κB) through the inhibition of phosphorylation of IκB kinase-α/β, phosphorylation and degradation of IκBα and nuclear translocation of p50 and p65. In addition, UVB-induced phosphorylation of p65 at the serine 276 residue was significantly inhibited by topical application of DHA. Irradiation with UVB induced phosphorylation of mitogen and stress-activated kinase-1 (MSK1), extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein (MAP) kinase, and all these events were attenuated by pretreatment with DHA. Blocking ERK and p38 MAP kinase signaling by U0126 and SB203580, respectively, diminished MSK1 phosphorylation in UVB-irradiated mouse skin. Pretreatment with H-89, a pharmacological inhibitor of MSK1, abrogated UVB-induced activation of NF-κB and the expression of COX-2 and NOX-4 in mouse skin. In conclusion, topically applied DHA inhibits the UVB-induced activation of NF-κB and the expression of COX-2 and NOX-4 by blocking the phosphorylation of MSK1, a kinase downstream of ERK and p38 MAP kinase, in hairless mouse skin.

There are multiple lines of evidence supporting that chronic inflammation is linked to carcinogenesis. Nuclear factor-kappaB (NF-kappaB), a major redox-sensitive transcription factor responsible for the induction of a wide array of pro-inflammatory genes, is frequently overactivated in many tumors. Moreover, constitutive activation of IkappaB kinase (IKK), a key regulator of NF-kappaB signaling, has been implicated in inflammation-associated tumorigenesis. Piceatannol (trans-3,4,3',5'-tetrahydroxystilbene; PIC) derived from grapes, rhubarb and sugarcane exhibits immunosuppressive and antitumorigenic activities in several cell lines, but the underlying mechanisms are poorly understood. In the present study, we found that PIC inhibited migration and anchorage-independent growth of human mammary epithelial cells (MCF-10A) treated with the prototypic tumor promoter, 12-O-tetradecanoylphorbol-13-aceate (TPA). PIC treatment suppressed the TPA-induced activation of NF-kappaB and expression of cyclooxygenase-2 (COX-2) in MCF-10A cells. We speculate that an electrophilic quinone formed as a consequence of oxidation of PIC bearing the catechol moiety may directly interact with critical cysteine thiols of IKKbeta, thereby inhibiting its catalytic activity. In support of this speculation, the reducing agent dithiothreitol abrogated the inhibitory effects of PIC on TPA-induced activation of NF-kappaB signaling and expression of COX-2. In addition, the inhibitory effects of PIC on NF-kappaB activation and COX-2 induction were blunted in cells expressing mutant IKKbeta (C179A) in which cysteine 179 was replaced by alanine. In conclusion, our results show that direct modification of IKKbeta by PIC, presumably at the cysteine 179 residue, blocks NF-kappaB activation signaling and COX-2 induction in TPA-treated MCF-10A cells and also migration and transformation of these cells.

An inverse relationship exists between the consumption of garlic and the risk of certain cancers. The present study was aimed at investigating the effect of garlic constituent diallyl trisulfide (DATS) on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced cyclooxygenase-2 (COX-2) expression and tumor promotion in mouse skin and to explore the underlying molecular mechanisms. Pretreatment of mouse skin with different garlic-derived allyl sulfides showed DATS to be the most potent in suppressing TPA-induced COX-2 expression. DATS significantly attenuated the DNA binding of activator protein-1 (AP-1), one of the transcription factors that regulate COX-2 expression, in TPA-stimulated mouse skin. DATS also diminished TPA-induced expression of c-Jun and c-Fos, the principal components of AP-1, and blunted the activation of c-Jun NH(2)-terminal kinase (JNK) and Akt. Pharmacologic inhibition of JNK or Akt by SP600125 or LY294002, respectively, resulted in diminished AP-1 DNA binding, reduced levels of c-Jun and c-Fos, and inhibition of COX-2 expression in TPA-treated mouse skin. The JNK or Akt kinase assay, taking c-Jun fusion protein as a substrate, revealed that TPA induced JNK- or Akt-mediated c-Jun phosphorylation in mouse skin, which was significantly attenuated by DATS or respective pharmacologic inhibitors. Evaluation of antitumor-promoting effect of DATS on 7,12-dimethylbenz(a)anthracene-initiated and TPA-promoted mouse skin carcinogenesis showed that pretreatment with DATS significantly reduced the incidence and multiplicity of papillomas. Taken together, the inhibitory effects of DATS on TPA-induced AP-1 activation and COX-2 expression through modulation of JNK or Akt signaling may partly account for its antitumor-promoting effect on mouse skin carcinogenesis.

There are multiple lines of compelling evidence supporting the beneficial effect of exercise on the prevention and/or improvement of certain chronic diseases. However, exhaustive or intense exercise causes oxygen free radical generation and oxidative stress, which can lead to injuries and chronic fatigue as well as inflammation. Abnormal upregulation of cyclooxygenase-2 (COX-2), a rate-limiting enzyme in prostaglandin biosynthesis, has been implicated in many inflammation-associated chronic disorders. Nuclear factor-kappaB (NF-kappaB) is a major transcription factor involved in regulation of COX-2 gene expression. To determine whether inflammation induction is dependent on intensity of exercise, COX-2 expression and NF-kappaB activation were adopted as the main targets. Thirteen volunteers who participated in the exercise program were subject to four exercise intensities [40, 60, 80, and 100% of heart rate reserve (HRR)] on a treadmill and to resting conditions. Isolated human peripheral blood mononuclear cells (PBMCs) were collected during the resting state and immediately after exercise and subjected to the electrophoretic mobility gel shift assay and Western blot analysis. As exercise intensity increased, both COX-2 expression and NF-kappaB DNA-binding activity were enhanced. The expression of IkappaB kinase alpha (IKKalpha) and IkappaBalpha were not significantly altered. However, exhaustive/vigorous exercise (100% HRR) could induce the phosphorylation of both IKKalpha and IkappaBalpha. In conclusion, a single bout of exercise induced COX-2 expression and DNA-binding activity of NF-kappaB in human PBMCs, and both COX-2 expression and DNA-binding activity of NF-kappaB were dependent on exercise intensity.

There are multiple lines of evidence supporting that inflammation is causally linked to carcinogenesis. Abnormal upregulation of cyclooxygenase-2 (COX-2), a rate-limiting enzyme in the prostaglandin biosynthesis, has been implicated in carcinogenesis. Trans-3,4,3',5'-tetrahydroxystilbene (piceatannol), a naturally occurring hydroxylated stilbene with potent anti-inflammatory and antioxidative activities, has been shown to inhibit the proliferation of several cancer cells by inducing apoptosis or blocking cell cycle progression. In this study, we examined the effect of piceatannol on activation of the nuclear transcription factor NF-kappa B, one of the major transcription factors that regulate proinflammatory COX-2 gene transcription, in human mammary epithelial (MCF-10A) cells treated with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). When pretreated to MCF-10A cells, piceatannol markedly inhibited TPA-induced NF-kappa B DNA binding to a greater extent than resveratrol and oxyresveratrol, stilbene analogs structurally related to piceatannol. Piceatannol also inhibited TPA-induced phosphorylation and degradation of Ikappa Balpha as well as nuclear translocation of the phosphorylated form of p65, the functionally active subunit of NF-kappa B. Likewise, TPA-induced expression of COX-2 was abrogated by piceatannol pretreatment. The thiol reducing agent dithiothreitol abolished the inhibitory effects of piceatannol on NF-kappa B DNA binding activity, suggesting that piceatannol may directly modify NF-kappa B or its regulator through reaction with the cysteine thiol(s).

Recent studies suggest that inflammation is causally linked to carcinogenesis. Cyclooxygenase-2 (COX-2), a rate-limiting enzyme in the biosynthesis of prostaglandins, is inappropriately expressed in various cancers and hence recognized as one of the hallmarks of chronic inflammation-associated malignancies. However, the mechanistic role of COX-2 as a link between inflammation and cancer remains undefined. Here, we report that 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), one of the final products of COX-mediated arachidonic acid metabolism, upregulates the expression of COX-2 in the human breast cancer MCF-7 cell line. 15d-PGJ(2)-induced COX-2 expression was mediated by activation of Akt and subsequently activator protein-1 (AP-1). Furthermore, 15d-PGJ(2) formed reactive oxygen species, which led to increased phosphorylation of Akt, DNA binding of AP-1 and expression of COX-2. In contrast to 15d-PGJ(2), 9,10-dihydro-15d-PGJ(2) did not elicit any of effects induced by 15d-PGJ(2) in this study, suggesting that an electrophilic carbon center present in 15d-PGJ(2) is critical for COX-2 expression as well activation of upstream signal transduction induced by this cyclopentenone prostaglandin. Taken together, these observations suggest that 15d-PGJ(2) produced by COX-2 overexpression may function as a positive regulator of COX-2 in human breast cancer MCF-7 cells.

Inappropriate up-regulation of cyclooxygenase-2 (COX-2) has been implicated in pathogenesis of various types of human cancer. Thus, COX-2 has been recognized as an important target for the chemoprevention of several human malignancies including breast cancer. COX-2 expression is known to be regulated by the eukaryotic transcription factor NF-kappaB. In an attempt to link the NF-kappaB activation and COX-2 induction during mammary carcinogenesis, we have examined the effects of 12-O-tetradecanoylphorbol-13-acetate (TPA), a prototype tumor promoter and a mitogen, on NF-kappaB activation and COX-2 expression in the immortalized human breast epithelial cell line (MCF10A). Treatment of MCF10A cells with TPA resulted in transient induction of NF-kappaB DNA binding with maximal activation observed at 30 min. Increased DNA binding of NF-kappaB was accompanied by enhancement of its transcriptional activity as determined by the luciferase reporter gene assay. Under the same experimental conditions, expression of COX-2 mRNA and its protein product peaked at 2h and 4h, respectively. TPA treatment caused an increase in the production of prostaglandin E(2). Treatment of cells with the NF-kappaB inhibitor pyrrolidine dithiocarbamate resulted in significant suppression of TPA-induced COX-2 expression. TPA induced activation of ERK1/2 and p38 mitogen-activated protein kinases (MAPK) via phosphorylation. PD98059 (ERK inhibitor) and SB203580 (p38 MAPK inhibitor) down-regulated the COX-2 expression induced by TPA. Furthermore, TPA-induced COX-2 induction as well as NF-kappaB activation was blocked in MCF10A cells transfected with dominant negative mutant ERK1/2 or p38 MAPK. These results suggest that both p38 and ERK MAPKs activates NF-kappaB signaling, which in turn induces COX-2 expression in TPA-stimulated human mammary epithelial cells.

We previously reported that a novel alkylphospholipid type antitumor agent edelfosine (ET-18-O-CH3 ; 1-O-octadecyl-2-O-methyl-glycero-3-phosphocholine) induced apoptosis in human breast epithelial cells transfected with the H-ras oncogene (MCF10A-ras) which was causally linked to cyclooxygenase-2 (COX-2) up-regulation and production of 15-deoxy-Delta 12,14-prostaglandins J2 (15d-PGJ2). ET-18-O-CH3 treatment also enhanced the production of prostaglandin E2 (PGE2), a major COX-2 product. In this study, we found that ET-18-O-CH3 treatment resulted in elevated mRNA expression of the PGE2 receptor subunit, EP2 receptor. Exogenously added PGE2 inhibited the growth of MCF10A-ras cells and induced proteolytic cleavage of caspase 3. ET-18-O-CH3 also inhibited constitutive activation of ERK1/2, p38 MAPK, and Akt/protein kinase B, which was blunted by a selective COX-2 inhibitor SC58635. In addition, ET-18-O-CH3 inhibited DNA binding activity of NF-kappa B in MCF10A-ras cells, and this was again attenuated by SC58635. Based on these findings, it is likely that ET-18-O-CH3 inactivates ERK1/2, Akt, and NF-kappaB signaling via COX-2 induction in MCF10A-ras cells, thereby inducing apoptosis of these cells.

Humulone, a bitter acid derived from hop (Humulus lupulus L.), possesses antioxidative, anti-inflammatory and other biologically active activities. Although humulone has been reported to inhibit chemically induced mouse skin tumor promotion, the underlying mechanisms are yet to be elucidated. Since an inappropriate over-expression of cyclooxygenase-2 (COX-2) is implicated in carcinogenesis, we investigated effects of humulone on COX-2 expression in mouse skin stimulated with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). Topical application of humulone (10 mumol) significantly inhibited TPA-induced epidermal COX-2 expression. Humulone also diminished TPA-induced DNA binding of nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1). Pre-treatment with humulone attenuated TPA-induced phosphorylation of p65 and nuclear translocation of NF-kappaB subunit proteins. Humulone blunted TPA-induced activation of inhibitory kappaB (IkappaB) kinase (IKK) in mouse skin, which accounts for its suppression of phosphorylation and subsequent degradation of IkappaBalpha. An in vitro kinase assay revealed that humulone could directly inhibit the catalytic activity of IKKbeta. Humulone suppressed the activation of mitogen-activated protein kinases (MAPKs) in TPA-treated mouse skin. The roles of extracellular signal-regulated protein kinase-1/2 and p38 MAPK in TPA-induced activation of NF-kappaB in mouse skin had been defined in our previous studies. The present study revealed that topical application of SP600125, a pharmacological inhibitor of c-Jun-N-terminal kinase (JNK), abrogated the activation of AP-1 and the expression of COX-2 in TPA-treated mouse skin. Taken together, humulone suppressed TPA-induced activation of NF-kappaB and AP-1 and subsequent expression of COX-2 by blocking upstream kinases IKK and JNK, respectively, which may account for its antitumor-promoting effects on mouse skin carcinogenesis.

Abnormally elevated expression of cyclooxygenase-2 (COX-2) has been frequently observed in transformed or malignant cells, and certain non-steroidal anti-inflammatory drugs with COX-2 inhibitory activity exert anti-neoplastic or chemopreventive effects. Contrary to this notion, we have found that a novel alkylphospholipid type antitumor agent ET-18-O-CH3 (1-O-octadecyl-2-O-methyl-glycero-3-phosphocholine) induces COX-2 expression in H-ras transformed human breast epithelial cells (MCF10A-ras) while it causes apoptosis at the same concentration range. The addition of a selective COX-2 inhibitor SC-58635 and COX-2 gene knock down with the siRNA blocked ET-18-O-CH3-induced apoptosis, suggesting that COX-2 induction by this drug is causally linked to its apoptosis inducing activity. ET-18-O-CH3 enhanced the transcriptional activities of cyclic AMP response element which is a key regulator of COX-2 expression. 15-Deoxy-Delta(12,14) prostaglandin J2 is, an endogenous ligand for peroxisome proliferator-activated receptor gamma (PPARgamma), has been known to possess proapoptotic potential in diverse cell types. ET-18-O-CH3 treatment resulted in elevated release of 15d-PGJ2 and DNA binding and transcriptional activity of PPARgamma. Based on these findings, it is likely that ET-18-O-CH3 induces COX-2 expression and production of 15d-PGJ2 which may mediate the ET-18-O-CH3-induced apoptosis in MCF10A-ras cells.

Abstract: Cyclooxygenase-2 (COX-2), a rate-limiting enzyme in arachidonic acid cascade, plays a key role in the biosynthesis of prostaglandin E2 (PGE2) upon inflammatory insults. Overproduction of PGE2 stimulates proliferation of various cancer cells, confers resistance to apoptosis of cancerous or transformed cells, and accelerates metastasis and angiogenesis. Excess PGE2 undergoes metabolic inactivation which is catalyzed by NAD+-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH). In this context, 15-PGDH has been speculated as a physiological antagonist of COX-2 and a tumor suppressor. Thus, overexpression of 15-PGDH has been known to protect against experimentally induced carcinogenesis and renders the cancerous or transformed cells susceptible to apoptosis by counteracting oncogenic action of PGE2. In contrast, silence of 15-PGDH is observed in some cancer cells, which is associated with epigenetic modification, such as DNA methylation and histone deacetylation, in the promoter region of 15-PGDH. A variety of compounds capable of inducing the expression of 15-PGDH have been reported, which include the histone deacetylase inhibitors, nonsteroidal anti-inflammatory drugs, and peroxisome proliferator-activated receptor-gamma agonists. Therefore, 15-PGDH may be considered as a novel molecular target for cancer chemoprevention and therapy. This review highlights the role of 15-PGDH in carcinogenesis and its regulation. [Copyright &y& Elsevier]

Abstract: 15-deoxy-Δ12,14-prostagandin J2 (15d-PGJ2) is produced in the inflamed cells and tissues as a consequence of upregulation of cyclooxygenase-2 (COX-2). 15d-PGJ2 is known to be the endogenous ligand of peroxisome proliferator-activated receptor gamma (PPARγ) with multiple physiological properties. Though one of the terminal products of the COX-2-catalyzed reactions, this cyclopentenone prostaglandin exerts potent anti-inflammatory actions, in part, by antagonizing the activities of pro-inflammatory transcription factors, such as NF-κB, STAT3, and AP-1, while stimulating the anti-inflammatory transcription factor Nrf2. These effects are not necessarily dependent on its activation of PPARγ, but often involves direct interaction with the above signaling molecules and their regulators. The locally produced 15d-PGJ2 is also involved in the resolution of inflammatory responses. Thus, 15d-PGJ2, especially formed during the late phase of inflammation, might inhibit cytokine secretion and other events by antigen-presenting cells like dendritic cells or macrophages. 15d-PGJ2 can also affect the priming and effector functions of T lymphocytes and induce their apoptotic cell death. These represent a negative feedback explaining how once-initiated immunologic and inflammatory responses are switched off and terminated. In this context, 15d-PGJ2 and its synthetic derivatives have therapeutic potential for the treatment of inflammatory disorders. [Copyright &y& Elsevier]

There are multiple lines of evidence supporting that inflammation is causally linked to carcinogenesis. Abnormal upregulation of cyclooxygenase-2 (COX-2), a rate-limiting enzyme in the prostaglandin biosynthesis, has been implicated in carcinogenesis. Trans-3,4,3',5'-tetrahydroxystilbene (piceatannol), a naturally occurring hydroxylated stilbene with potent anti-inflammatory and antioxidative activities, has been shown to inhibit the proliferation of several cancer cells by inducing apoptosis or blocking cell cycle progression. In this study, we examined the effect of piceatannol on activation of the nuclear transcription factor NF-κ B, one of the major transcription factors that regulate proinflammatory COX-2 gene transcription, in human mammary epithelial (MCF-10A) cells treated with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). When pretreated to MCF-10A cells, piceatannol markedly inhibited TPA-induced NF-κ B DNA binding to a greater extent than resveratrol and oxyresveratrol, stilbene analogs structurally related to piceatannol. Piceatannol also inhibited TPA-induced phosphorylation and degradation of Iκ Bα as well as nuclear translocation of the phosphorylated form of p65, the functionally active subunit of NF-κ B. Likewise, TPA-induced expression of COX-2 was abrogated by piceatannol pretreatment. The thiol reducing agent dithiothreitol abolished the inhibitory effects of piceatannol on NF-κ B DNA binding activity, suggesting that piceatannol may directly modify NF-κ B or its regulator through reaction with the cysteine thiol(s). [ABSTRACT FROM AUTHOR]

There are multiple lines of compelling evidence supporting the beneficial effect of exercise on the prevention and/or improvement of certain chronic diseases. However, exhaustive or intense exercise causes oxygen free radical generation and oxidative stress, which can lead to injuries and chronic fatigue as well as inflammation. Abnormal upregulation of cyclooxygenase-2 (COX-2), a rate-limiting enzyme in prostaglandin biosynthesis, has been implicated in many inflammation-associated chronic disorders. Nuclear factor-κB (NF-κB) is a major transcription factor involved in regulation of COX-2 gene expression. To determine whether inflammation induction is dependent on intensity of exercise, COX-2 expression and NF-κB activation were adopted as the main targets. Thirteen volunteers who participated in the exercise program were subject to four exercise intensities [40, 60, 80, and 100% of heart rate reserve (HRR)] on a treadmill and to resting conditions. Isolated human peripheral blood mononuclear cells (PBMCs) were collected during the resting state and immediately after exercise and subjected to the electrophoretic mobility gel shift assay and Western blot analysis. As exercise intensity increased, both COX-2 expression and NF-κB DNA-binding activity were enhanced. The expression of IκB kinase α (IKKα) and IκBα were not significantly altered. However, exhaustive/vigorous exercise (100% HRR) could induce the phosphorylation of both IKKα and IκBα. In conclusion, a single bout of exercise induced COX-2 expression and DNA-binding activity of NF-κB in human PBMCs, and both COX-2 expression and DNA-binding activity of NF-κB were dependent on exercise intensity. [ABSTRACT FROM AUTHOR]

Ginsenosides, ingredients of ginseng, have a wide array of pharmacologic effects. Especially, ginsenosides Rk1, Rg3, and Rg5 derived from heat-processed ginseng have been shown to possess substantial anti-tumor-promoting effects. KG-135 is a formulated complex that contains several antitumorigenic ginsenosides, such as Rk1, Rg3, Rg5, Rk2, Rk3, Rs3, Rs4, Rs5, Rs6, Rs7, etc. The present article was aimed at evaluating the chemopreventive as well as anti-inflammatory effects of KG-135 in the human breast epithelial cell line (MCF-10A). One of the well-recognized molecular targets for chemoprevention is cyclooxygenase-2 (COX-2) that is abnormally upregulated in many premalignant and malignant tissues and cells. In this study, we found that KG-135 inhibited COX-2 expression in MCF-10A cells stimulated with a prototype tumor promotor 12- O-tetradecanoylphorbol-13-acetate (TPA). Since the transcription factor activator protein-1 (AP-1) plays a role in tumor promotion and is also known to regulate COX-2 induction, we attempted to determine the effect of KG-135 on TPA-induced activation of AP-1. Cotreatment with KG-135 resulted in a decrease in TPA-induced DNA binding of AP-1. In addition, KG-135 inhibited TPA-induced phosphorylation of c-Jun N-terminal kinases (JNK) that regulates COX-2 expression in MCF-10A cells. The JNK inhibitor SP600125 attenuated COX-2 expression in TPA-treated MCF-10A cells. Taken together, the above findings suggest that KG-135 inhibits TPA-induced COX-2 expression in MCF-10A cells by blocking the JNK/AP-1 signaling pathway. [ABSTRACT FROM AUTHOR]

Overproduction of prostaglandin E 2 (PGE 2 ) has been reported to be implicated in carcinogenesis. The intracellular level of PGE 2 is maintained not only by its biosynthesis, but also by inactivation/degradation. 15-Hydroxyprostaglandin dehydrogenase (15-PGDH) is the key enzyme that catalyzes the conversion of oncogenic PGE 2 to a biologically inactive keto metabolite. In the present study, we demonstrate that 15-deoxy-Δ 12,14 -prostaglandin J 2 (15d-PGJ 2 ), one of the terminal products of cyclooxygenase-2, updregulates the expression and the activity of 15-PGDH in human breast cancer MDA-MB-231 cells. By using deletion constructs of the 15-PGDH promoter, we have found that E-twenty six (Ets) is the most essential determinant for 15-PGDH induction. 15d-PGJ 2 induced phosphorylation of Elk-1, one of Ets transcription factor family members, in the nucleus. Knockdown of Elk-1 abolished the ability of 15d-PGJ 2 to upregulate 15-PGDH expression. Furthermore, 15d-PGJ 2 -mediated activation of Elk-1 was found to be dependent on activation of extracellular-signal related kinase (ERK) 1/2. Treatment of U0126, a pharmacological inhibitor of MEK1/2-ERK, abolished phosphorylation and DNA binding of Elk-1 as well as 15-PGDH induction in 15d-PGJ 2 -treated MDA-MB-231 cells. Moreover, 15d-PGJ 2 generated reactive oxygen species (ROS), which contribute to the expression of 15-PGDH as well as phosphorylation of ERK1/2 and Elk-1. 15d-PGJ 2 inhibited the migration of MDA-MB-231 cells, which was attenuated by transient transfection with 15-PGDH siRNA. Taken together, these findings suggest that 15d-PGJ 2 induces the expression of 15-PGDH through ROS-mediated activation of ERK1/2 and subsequently Elk-1 in the MDA-MB-231 cells, which may contribute to tumor suppressive activity of this cyclopentenone prostaglandin. [ABSTRACT FROM AUTHOR]