Docosahexaenoic Acid Inhibits UVB-Induced Activation of NF-κB and Expression of COX-2 and NOX-4 in HR-1 Hairless Mouse Skin by Blocking MSK1 Signaling

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

Cyclooxygenase-2 신호전달을 타깃으로 하는 EGCG, resveratrol과 oligonol의 마우스 피부암 억제 기전

Thesis(doctor`s)--서울대학교 대학원 :약학과 생물화학전공,2006.Docto

Signal transduction network leading to COX-2 induction: A road map in search of cancer chemopreventives

Cancer is still a major global health concern even after an everlasting strive in conquering this dread disease. Emphasis is now given to chemoprevention to reduce the risk of cancer and also to improve the quality of life among cancer afflicted individuals. Recent progress in molecular biology of cancer has identified key components of the cellular signaling network, whose functional abnormality results in undesired alterations in cellular homeostasis. creating a cellular microenvironment that favors premalignant and malignant transformation. Multiple fines of, evidence suggest an elevated expression of cyclooxygenase-2 (COX-2) is causally linked to cancer. In response to oxidative/pro-inflammatory stimuli, turning on unusual signaling arrays mediated through diverse classes of kinases and transcription factors results in aberrant expression of COX-2. Population-based as well as laboratory studies have explored a broad spectrum of chemopreventive agents including selective COX-2 inhibitors and a wide variety of, anti-inflammatory phytochemicals, which have been shown to target cellular signaling molecules as underlying mechanisms of chemoprevention. Thus, unraveling signaling pathways regulating aberrant COX-2 expression and targeted blocking of one or more components or those signal cascades may be exploited in searching chemopreventive agents in the future

Molecular basis of chemoprevention by resveratrol: NF-κB and AP-1 as potential targets

Recently, chemoprevention by the use of naturally occurring substances is considered as a priority to reduce the ever-increasing incidence of cancer. The intervention of multistage carcinogenesis by modulating intracellular signaling pathways may provide molecular basis of chemoprevention with a wide variety of dietary phytochemicals. Resveratrol, a red wine polyphenol, has been studied extensively for the chemopreventive activity in the context of its ability to interfere with the multistage carcinogenesis. Numerous intracellular signaling cascades converge with the activation of nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1), which act independently or coordinately to regulate expression of target genes. These ubiquitous eukaryotic transcription factors mediate pleiotropic effects on cellular transformation and tumor promotion. This review aims to update the molecular mechanisms underlying chernoprevention by resveratrol with special focus on its effect on cellular signaling cascades mediated by NF-kappaB and AP-1. (C) 2004 Elsevier B.V. All rights reserved

Emerging avenues linking inflammation and cancer

The role of inflammation in carcinogenesis has been extensively investigated and well documented. Many biochemical processes that are altered during chronic inflammation have been implicated in tumorigenesis. These include shifting cellular redox balance toward oxidative stress; induction of genomic instability; increased DNA damage; stimulation of cell proliferation, metastasis, and angiogenesis; deregulation of cellular epigenetic control of gene expression; and inappropriate epithelial-to-mesenchymal transition. A wide array of proinflammatory cytokines, prostaglandins, nitric oxide, and matricellular proteins are closely involved in premalignant and malignant conversion of cells in a background of chronic inflammation. Inappropriate transcription of genes encoding inflammatory mediators, survival factors, and angiogenic and metastatic proteins is the key molecular event in linking inflammation and cancer. Aberrant cell signaling pathways comprising various kinases and their downstream transcription factors have been identified as the major contributors in abnormal gene expression associated with inflammation-driven carcinogenesis. The posttranscriptional regulation of gene expression by microRNAs also provides the molecular basis for linking inflammation to cancer. This review highlights the multifaceted role of inflammation in carcinogenesis in the context of altered cellular redox signaling. (c) 2012 Elsevier Inc. All rights reserved

Cancer preventive phytochemicals as speed breakers in inflammatory signaling involved in aberrant COX-2 expression

A causal association between inflammation and cancer has long been suspected. Multiple lines of compelling evidence from clinical, epiderniologic and laboratory studies support that inflammation plays a critical role in the promotion and progression stages of carcinogenesis. Recent progress in our understanding of the molecular biology of cancer highlights the intracellular signal transduction network, including-that involved in mediating the inflammatory response, which often functions abnormally during carcinogenesis. One of the key players in inflammatory signaling is cyclooxygenase-2 (COX-2). Aberrant upregulation of COX-2 is frequently observed in various precancerous and malignant tissues. Pro-inflammatory stimuli trigger the activation of an intracellular signal transduction network comprising proline-directed serine/threonine kinases, and their downstream transcription factors, resulting in an inappropriate induction of COX-2. Therefore, the normalization of inappropriately overamplified signaling cascades implicated in chronic inflammation-associated carcinogenesis by use of COX-2 specific inhibitors has been recognized as a rational and pragmatic strategy in molecular target-based cancer prevention. This review highlights the cancer preventive effects of some anti- in flammato ry phytochemicals derived from edible plants, and their underlying molecular mechanisms with a focus on representative transcription factors and upstream kinases responsible for COX-2 induction

Inflammation: Gearing the journey to cancer

Chronic inflammation plays a multifaceted role in carcinogenesis. Mounting evidence from preclinical and clinical studies suggests that persistent inflammation functions as a driving force in the journey to cancer. The possible mechanisms by which inflammation can contribute to carcinogenesis include induction of genomic instability, alterations in epigenetic events and subsequent inappropriate gene expression, enhanced proliferation of initiated cells, resistance to apoptosis, aggressive tumor neovascularization, invasion through tumor-associated basement membrane and metastasis, etc. Inflammation-induced reactive oxygen and nitrogen species cause damage to important cellular components (e.g., DNA, proteins and lipids), which can directly or indirectly contribute to malignant cell transformation. Overexpression, elevated secretion, or abnormal activation of proinflammatory mediators, such as cytokines, chemokines, cyclooxygenase-2, prostaglandins, inducible nitric oxide synthase, and nitric oxide, and a distinct network of intracellular signaling molecules including upstream kinases and transcription factors facilitate tumor promotion and progression. While inflammation promotes development of cancer, components of the tumor microenvironment, such as tumor cells, stromal cells in surrounding tissue and infiltrated inflammatory/immune cells generate an intratumoral inflammatory state by aberrant expression or activation of some proinflammatory molecules. Many of proinflammatory mediators, especially cytokines, chemokines and prostaglandins, turn on the angiogenic switches mainly controlled by vascular endothelial growth factor, thereby inducing inflammatory angiogenesis and tumor cell-stroma communication. This will end up with tumor angiogenesis, metastasis and invasion. Moreover, cellular microRNAs are emerging as a potential link between inflammation and cancer. The present article highlights the role of various proinflammatory mediators in carcinogenesis and their promise as potential targets for chemoprevention of inflammation-associated carcinogenesis. (C) 2008 Elsevier B.V. All rights reserved

Nrf2-keap1 signaling as a potential target for chemoprevention of inflammation-associated carcinogenesis

Persistent inflammatory tissue damage is causally associated with each stage of carcinogenesis. Inflammation-induced generation of reactive oxygen species, reactive nitrogen species, and other reactive species not only cause DNA damage and subsequently mutations, but also stimulate proliferation of initiated cells and even metastasis and angiogenesis. Induction of cellular cytoprotective enzymes (e.g., heme oxygenase-1, NAD(P)H:quinone oxidoreductase, superoxide dismutase, glutathione-S-transferase, etc.) has been shown to mitigate aforementioned events implicated in inflammation-induced carcinogenesis. A unique feature of genes encoding these cytoprotective enzymes is the presence of a cis-acting element, known as antioxidant response element (ARE) or electrophile response element (EpRE), in their promoter region. A stress-responsive transcription factor, nuclear factor erythroid-2-related factor-2 (Nrf2), initially recognized as a key transcriptional regulator of various cytoprotective enzymes, is known to play a pivotal role in cellular defense against inflammatory injuries. Activation of Nrf2 involves its release from the cytosolic repressor Kelch-like ECH-associated protein-1 (Keap1) and subsequent stabilization and nuclear localization for ARE/EpRE binding. Genetic or pharmacologic inactivation of Nrf2 has been shown to abolish cytoprotective capability and to aggravate experimentally induced inflammatory injuries. Thus, Nrf2-mediated cytoprotective gene induction is an effective strategy for the chemoprevention of inflammation-associated carcinogenesis

Epigallocatechin Gallate inhibits phorbol ester-induced activation of NF-κB and CREB in mouse skin role of p38 MAPK

The modulation of intracellular signaling network involved in an inappropriate expression of cyclooxygenase-2- (COX-2) is a pragmatic approach for chemoprevention with a wide variety of dietary phytochemicals. Epigallocatechin gallate (EGCG), a major green tea polyphenol, is one of the most extensively investigated chemopreventive agents. Our previous study revealed that EGCG inhibited expression of COX-2 and activation of mitogen-activated protein kinases (MAPKs) in mouse skin stimulated with a prototype tumor promotor 12-O-tetradecanoylphorbol-13-acetate (TPA). This study was aimed at identifying transcription factors as molecular targets of EGCG in downregulating COX-2 expression. We found that EGCG inhibited TPA-induced DNA binding of NF-kappa B and CREB in mouse skin in vivo. EGCG also suppressed TPA-induced phosphorylation and subsequent degradation of I kappa B alpha, and prevented nuclear translocation of p65. We also examined whether extracellular signal-regulated protein kinase (ERK) and p38 MAPK, which are known to regulate activation of NF-kappa B, can also modulate CREB DNA binding. Pretreatment with U0126 and SB203580, pharmacological inhibitors of ERK and p38 MAPK, respectively, showed that SB203580, but not U0126, attenuated TPA-induced CREB DNA binding in mouse skin. Taken together, EGCG inhibited TPA-induced DNA binding of NF-kappa B and CREB by blocking activation of p38 MAPK, which may provide a molecular basis of COX-2 inhibition by EGCG in mouse skin in vivo

Cancer chemopreventive and therapeutic potential of resveratrol: Mechanistic perspectives

A plant kingdom is considered as a gold mine for the discovery of many biologically active substances with therapeutic values. Resveratrol (3,5,4'-trihydroxystilbene), a naturally occurring polyphenol, exhibits pleiotropic health beneficial effects including anti-oxidant, anti-inflammatory, cardioprotective and anti-tumor activities. Currently, numerous preclinical findings suggest resveratrol as a promising nature's arsenal for cancer prevention and treatment. A remarkable progress in dissecting the molecular mechanisms underlying anti-cancer properties of resveratrol has been achieved in the past decade. As a potential anti-cancer agent, resveratrol has been shown to inhibit or retard the growth of various cancer cells in culture and implanted tumors in vivo. The compound significantly inhibits experimental tumorigenesis in a wide range of animal models. Resveratrol targets many components of intracellular signaling pathways including pro-inflammatory mediators, regulators of cell survival and apoptosis, and tumor angiogenic and metastatic switches by modulating a distinct set of upstream kinases, transcription factors and their regulators. This review summarizes the diverse molecular targets of resveratrol with a special focus on those involved in fine-tuning of orchestrated intracellular signal transduction. (C) 2008 Elsevier Ireland Ltd. All rights reserved