Piceatannol, a catechol-type polyphenol, inhibits phorbol ester-induced NF-kB activation and cyclooxygenase-2 expression in human breast epithelial cells.

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Piceatannol, a catechol-type polyphenol, inhibits phorbol ester-induced NF-kB activation and cyclooxygenase-2 expression in human breast epithelial cells : cysteine 179 of IKKb as a potential target Pil-Soon Son, Sin-Aye Park, Hye-Kyung Na, Dae-Myung Jue, Sanghee Kim and Young-Joon Surh Team : TYPE O Shim, Jae-seung/Lee, Dong-jae/Byun, Ki-tae /Bang, Mi-ra KonKuk University Carcinogenesis vol.31 no.8 pp.1442–1449, 2010 doi: /carcin/bgq099 Advance Access publication June 27, 2010

1. INTRODUCTION-Concept 1. COX-2 (Pro-inflammatory enzymes) Inducible by various inflammatory stimuli, including tumor promoters, growth factors, pro-inflammatory cytokines, bacterial toxins and reactive oxygen species. 2. NF-kB (Transcription factors) - Responsible for regulating cox-2 gene transcription. - P lays a key role in regulating the immune response to infection. 3. IKK (IkB kinase, Potential target) - Present c ysteine residues in the kinase domain of IKKa(Cys178) and IKKb (Cys179). - Responsible for redox regulation of NF-kB activation.

1. INTRODUCTION-Concept NF-kB I-kB binding Virus, chemicals … IKK (cysteine 179) I-kB NF-kB P P COX-2 (Pro-inflammatory enzyme)

1. INTRODUCTION-Suppression Resveratrol - A common phytoalexin found in grapes, mulberries and other edible plants - Antioxidant, anti-inflammatory,anti- aging, cardioprotective, neuroprotective activities - Suppression of the inflammatory response by blocking expression or activity of pro-inflammatory enzymes, such as cyclooxygense-2 (COX-2) is primarily regulated by nuclear factor-kB (NF- k B)

1. INTRODUCTION-Suppression Piceatannol - A polyphenol found in grapes, rhubarb. - A protein kinase inhibitor that modulates multiple targets and elicits antioxidant, immunosuppressive and antiinflammatory effects. - Exert an inhibitory effect on tumor necrosis factor-induced NF-kB activation and NF-kB-mediated gene expression

1. INTRODUCTION-Suppression

IKKb (cysteine 179) NF-kB The inflammatory response COX-2 1. INTRODUCTION-Experiment Piceatannol

Investigated PIC-mediated inhibition of NF-kB signaling in human breast epithelial cells stimulated with the tumor promoter TPA. Present evidence supporting that PIC can block NF-kB signaling by interacting with an IKKb, presumably at Cys179 inhibiting migration and anchorage-independent growth of these cells.

2. MATERIALS & METHODS Materials - Resveratrol, Oxyresveratrol, PIC, TPA, DTT, Antibody(COX-2, pIkBa, IKKb, phosphor-IKKa/b) etc.Methods - Cell culture (MCF-10A cells) - Western blot analysis - In vitro IKK activity assay (radioactive) - Anchorage-independent growth assay - Wound healing assay

3. RESULTS RESULTS -1 - PIC strongly inhibited TPA-induced IKKb kinase activity and phosphorylation of IkBa. - PIC inhibited TPA-induced IKKb kinase activity and IKKa/b phosphorylation. ▶ Fig.1. Comparative effects of PIC and its analogs on TPA-induced IKKb activity.

3. RESULTS RESULTS -2 The reducing agent DTT(dithiothreitol) abrogated the PIC- mediated suppression of IKK–NF-kB signaling and COX-2 induction. ▶ Fig.2. The abrogation of the inhibitory effect of PIC on TPA-induced IKKb activity.

3. RESULTS RESULTS -3 PIC directly inhibited IKKb activity. ▶ Fig. 3. Direct inhibition of TPA-induced IKKb activity in MCF-10A cells by PIC.

3. RESULTS RESULTS -4 PIC inhibited NF-kB signaling through direct interaction possibly with cysteine 179 in IKKb. ▶ Fig. 4. Cysteine 179 of IKKb as a putative target of PIC for suppression of IKKb activity.

3. RESULTS RESULTS -4 - PIC repressed TPA-induced cell migration. - PIC abrogated the TPA-induced cell transformation. ▶ Fig. 5. The inhibitory effect of PIC on TPA-induced migration.

4. DISCUSSION PIC was found to be more effective in suppressing IKK–NF-kB signaling than the other compounds. (Resveratrol) PIC inhibits TPA-induced IKKb activity in MCF- 10A cells presumably by targeting the Cys179 residue located in the activation loop of IKKb. This results in down-regulation of TPA-induced expression of COX-2 and cell migration and transformation induced by TPA.

4. DISCUSSION PIC might be oxidized by enzymes such as peroxidases or cytochrome P450s (CYPs). An electrophilic quinone formed as a consequence of oxidation of PIC may directly interact with a critical cysteine thiol of IKKb, especially Cys179. PIC has a chemopreventive potential against inflammationassociated carcinogenesis in which the IKK–NF-kB signaling axis plays a predominant role.