Abstract CN07-01: Modulation of proinflammatory and anti-inflammatory signaling for cancer chemoprevention

Abstract

Abstract A new horizon in chemoprevention research is the recent discovery of molecular links between inflammation and cancer. The implication of inflammatory tissue damage in pathophysiology of human maligancy is under intense investigation both at the research level and in clinical practice. Numerous studies have been reported with the global ‘omics’ profiling technologies, such as DNA microarray, proteomics, metabolomics, lipidomics, etc., to identify and characterize a series of critical molecules/changes in the inflammatory signaling. It is by gaining this type of mechanistic understanding of a disease that researchers will unlock the keys to discovering new diagnostics and therapeutic strategies for the management of inflammation-associated cancer. Aberrant upregulation of cyclooxygenase-2 (COX-2), a key enzyme in the arachidonic acid cascade, has been frequently observed in various precancerous and malignant tissues. 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 chemoprevention. Proinflammatory stimuli trigger the activation of intracellular signal transduction network comprising proline-directed serine/threonine kinases, and their downstream transcription factors, such as NF-κB, resulting in an overexpression of COX-2. Cyclopentenone prostaglandins of J series as products of cyclooxygenase-2 (COX-2)-mediated arachidonic acid cascades have been reported to possess multifaceted cellular functions, including antiinflammatory and cytoprotective effects. A typical example is 15-deoxy-Δ 12,14-prostaglandin J2 (15d-PGJ2), an endogenous ligand of peroxisome proliferator-activated receptor-γ (PPARγ), that modulates the activities of various intracellular signaling molecules. Because of the electrophilic α,β-unsaturated carbonyl moiety present in its cyclopentenone ring structure, 15d-PGJ2 acts as a Michael addition acceptor and can readily interact with critical cellular nucleophiles, such as cysteine thiol groups of proteins. Many of the biological effects induced by 15d-PGJ2 are mediated by targeting redox-sensitive transcription factors and their regulators, including IκB kinase-NF-κB, AP-1, Nrf2-Keap1, HIF-1α, STAT3and p53 tumor suppressor. The regulation of the aforementioned signaling molecules by 15d-PGJ2 is not likely to be dependent on PPARγ activation, but rather involves direct modification or oxidation of their critical cysteine residues acting as a redox-sensor. Though 15d-PGJ2 exerts cytoprotective effects in normal cells, elevated production of this cyclopentenone prostaglandin has been implicated in tumorigenesis through induction of angiogenesis and metastasis. As one of the terminal products of COX-2-mediated arachidonic acid metabolism, 15d-PGJ2 upregulates the expression of COX-2 in the human breast cancer MCF-7 cell line by activation of Akt and subsequently AP-1. Some malignant cells might exploit this visious cycle of COX-2 up-expression for maintaining invasiveness and taking survival advantage. Cysteine thiols present in various transcription factors and their regulators function as redox sensors in fine-tuning of transcriptional regulation. Thus, oxidation or covalent modification of thiol groups present in the redox-sensitive transcription factors and their regulating molecules can provide a unique strategy for molecular target-based chemoprevention. Citation Information: Cancer Prev Res 2011;4(10 Suppl):CN07-01.