Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
Reviewβ-catenin-mediated signaling: A novel molecular target for chemoprevention with anti-inflammatory substances
Introduction
Chemoprevention is a non-invasive and cost-effective strategy in reducing cancer associated morbidity and mortality. The term ‘chemoprevention’ refers to the use of non-toxic substances to delay, reverse or suppress multistage carcinogenesis [1]. In spite of immense advances in the understanding of pathophysiology of cancer and development of new anticancer therapies, the mortality resulting from common forms of cancer is still unacceptably high. Chemoprevention offers a unique scope to intervene in each stage of carcinogenesis by a wide variety of substances of either natural or synthetic origin [1]. As inflammation is causally linked to cancer [2], substances with potent anti-inflammatory activities are anticipated to exert chemopreventive effects. Recent progress in unraveling intracellular signaling networks that contribute to multistage carcinogenesis has made it possible to identify signal transducing molecules or events as potential targets for chemoprevention [1].
Although enzymes mediating inflammatory response such as cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) have been identified as molecular targets for the prevention of cancer by anti-inflammatory substances [3], cellular signaling network linking inflammation and carcinogenesis has not been fully elucidated. Recently, activation of a eukaryotic transcription factor nuclear factor-κB (NF-κB) has been recognized as a bridge between inflammation and cancer [2]. Besides NF-κB, the activation of an evolutionarily conserved signaling pathways amplified by soluble Wnt ligands, which are secreted by activated macrophages [4], has been implicated in creating such a link. An inappropriate activation of Wnt-signaling contributes to cellular proliferation through up-regulation of T Cell Factor (TCF)/β-catenin-regulated transcription of various proliferative genes [5].
Chronic inflammation-associated accumulation of β-catenin in prostate cancer suggests that β-catenin may act as a potential link between inflammation and cancer [6]. β-catenin has been shown to function as a signaling molecule involved in the process of development, proliferation and differentiation [7]. Multiple lines of evidences suggest that stabilization and subsequent nuclear accumulation of β-catenin are positively linked to various human malignancies [5], [8], [9], [10], [11]. Several recent studies have also demonstrated β-catenin as a putative regulator of COX-2 [12], [13], [14], suggesting β-catenin as a potential target for chemoprevention by anti-inflammatory substances. The present review focuses on the modulation of β-catenin-mediated signaling as a plausible mechanism of chemoprevention by various anti-inflammatory substances.
Section snippets
Migration of membrane-bound β-catenin to cytosol
The multifunctional protein β-catenin exists in different subcellular locations depending upon physiological conditions or cellular environment including cell density [15], types of cells [16], [17], interaction with other signaling molecules [18], [19], [20], disease status [21], [22], [23], etc. While the membrane bound β-catenin interacts with the cytosolic tail of E-cadherin and connects actin filaments through α-catenin to form cytoskeleton, the free cytosolic form predominantly
Role of β-catenin-mediated signaling in carcinogenesis
Accumulating data from both in vitro and in vivo studies suggest the implication of β-catenin-mediated signaling in tumorigenesis [76], [77], [78], [79], [80]. Cytosolic stabilization and subsequent nuclear translocation of β-catenin resulting in transcriptional activation of a variety of TCF-regulated proliferative genes and oncogenes appear to be a potential cause of various human cancers [5], [9], [10], [78], [81], [82], [83], [84], [85]. The contributory role of aberrant β-catenin
Down-regulation of inappropriately activated β-catenin-mediated signaling by anti-inflammatory substances
Since inflammation is causally linked to carcinogenesis, substances with potent anti-inflammatory activities are anticipated to exert chemopreventive effects [1], [113]. Accumulating evidence from epidemiologic, clinical and laboratory studies suggests that nonsteroidal anti-inflammatory agents (NSAIDs) as well as naturally occurring anti-inflammatory substances are able to prevent certain forms of cancers [114], [115]. Progress in the understanding of molecular mechanisms of chemoprevention by
Future perspectives
Although inappropriate β-catenin-mediated signaling has been largely implicated in colorectal carcinogenesis, recent studies suggest that β-catenin acts as a key player in other forms of cancer. A prototype tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) has been reported to mediate tyrosine phosphorylation of β-catenin of E-cadherin–β-catenin complex in the human rectal adenocarcinoma cell line RCM-1 [141]. Furthermore, the treatment of mouse skin with 7,12-dimethylbenz[a]anthracene
Acknowledgements
This work was supported by the National Research Laboratory (NRL) Grant from the Ministry of Science and Technology, Republic of Korea.
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