Modulation of Key Elements of the Wnt Pathway by Apple Polyphenols
Glycogen synthase kinase-3β (GSK3β) is one of the key elements of the Wnt pathway involved in the regulation of β-catenin homeostasis. The inhibition of GSK3β kinase activity might lead to the onset of β-catenin/TCF/LEF-mediated gene transcription, representing a potentially mitogenic stimulus. Appl...
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| Veröffentlicht in: | Journal of agricultural and food chemistry 2006-09, Vol.54 (19), p.7041-7046 |
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| creator | Kern, Melanie Pahlke, Gudrun Ngiewih, Yufanyi Marko, Doris |
| description | Glycogen synthase kinase-3β (GSK3β) is one of the key elements of the Wnt pathway involved in the regulation of β-catenin homeostasis. The inhibition of GSK3β kinase activity might lead to the onset of β-catenin/TCF/LEF-mediated gene transcription, representing a potentially mitogenic stimulus. Apple polyphenols have been shown to mediate several biological effects that might be of interest with respect to chemoprevention. The objective of the study was to elucidate whether apple polyphenols also modulate key elements of the Wnt pathway, an effect that might limit the usefulness of these compounds for the prevention of carcinogenesis. A polyphenol-rich apple juice extract (AE02) was found to effectively inhibit the kinase activity of GSK3β, immunoprecipitated from HT29 cells. Treatment of HT29 cells with AE02 for 24 h resulted in a concentration-dependent decrease of the cellular GSK3β kinase activity. The inhibition of the kinase activity in HT29 cells was observed at polyphenol concentrations corresponding to the concentration of the constituents in the original apple juice. The apple characteristic dihydrochalcone glycoside phloridzin was found to be inactive up to 500 μM. The free aglycon phloretin as well as the flavonol quercetin effectively inhibited isolated GSK3β, but did not affect the respective kinase activity within HT29 cells. In accordance with the inhibition of GSK3β kinase activity by AE02, treatment of HT29 cells resulted in a significant decrease of phosphorylated β-catenin. However, the total intracellular β-catenin level was also found to be diminished, indicating that the interference of the apple constituents with GSK3β was not associated with a stabilization of β-catenin in HT29 cells. In line with these results, TCF/LEF-mediated gene transcription remained unaffected by treatment with AE02 as shown in a reporter gene approach. We can assume from the results that at consumer-relevant concentrations apple polyphenols do not mediate growth-stimulating effects in HT29 cells via the Wnt pathway. Keywords: Phloretin; phloridzin; quercetin; glycogen synthase kinase-3β; β-catenin; colon carcinoma; HT29 |
| doi_str_mv | 10.1021/jf0606611 |
| format | Article |
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The inhibition of GSK3β kinase activity might lead to the onset of β-catenin/TCF/LEF-mediated gene transcription, representing a potentially mitogenic stimulus. Apple polyphenols have been shown to mediate several biological effects that might be of interest with respect to chemoprevention. The objective of the study was to elucidate whether apple polyphenols also modulate key elements of the Wnt pathway, an effect that might limit the usefulness of these compounds for the prevention of carcinogenesis. A polyphenol-rich apple juice extract (AE02) was found to effectively inhibit the kinase activity of GSK3β, immunoprecipitated from HT29 cells. Treatment of HT29 cells with AE02 for 24 h resulted in a concentration-dependent decrease of the cellular GSK3β kinase activity. The inhibition of the kinase activity in HT29 cells was observed at polyphenol concentrations corresponding to the concentration of the constituents in the original apple juice. The apple characteristic dihydrochalcone glycoside phloridzin was found to be inactive up to 500 μM. The free aglycon phloretin as well as the flavonol quercetin effectively inhibited isolated GSK3β, but did not affect the respective kinase activity within HT29 cells. In accordance with the inhibition of GSK3β kinase activity by AE02, treatment of HT29 cells resulted in a significant decrease of phosphorylated β-catenin. However, the total intracellular β-catenin level was also found to be diminished, indicating that the interference of the apple constituents with GSK3β was not associated with a stabilization of β-catenin in HT29 cells. In line with these results, TCF/LEF-mediated gene transcription remained unaffected by treatment with AE02 as shown in a reporter gene approach. We can assume from the results that at consumer-relevant concentrations apple polyphenols do not mediate growth-stimulating effects in HT29 cells via the Wnt pathway. Keywords: Phloretin; phloridzin; quercetin; glycogen synthase kinase-3β; β-catenin; colon carcinoma; HT29</description><identifier>ISSN: 0021-8561</identifier><identifier>EISSN: 1520-5118</identifier><identifier>DOI: 10.1021/jf0606611</identifier><identifier>PMID: 16968061</identifier><identifier>CODEN: JAFCAU</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>apple juice ; apples ; beta Catenin - metabolism ; biochemical pathways ; Biological and medical sciences ; Blotting, Western ; carcinogenesis ; colorectal neoplasms ; disease prevention ; enzyme activity ; enzyme inhibitors ; Flavonoids - pharmacology ; food composition ; Food industries ; Fruit - chemistry ; Fruit and vegetable industries ; Fundamental and applied biological sciences. Psychology ; gene expression ; Glycogen Synthase Kinase 3 - antagonists & inhibitors ; Glycogen Synthase Kinase 3 beta ; Homeostasis ; HT29 Cells ; Humans ; Immunosorbent Techniques ; Malus - chemistry ; Phenols - pharmacology ; Polyphenols ; Protein Kinase Inhibitors - pharmacology ; protein kinases ; reporter genes ; Transcription, Genetic - drug effects ; Wnt pathway ; Wnt Proteins - metabolism</subject><ispartof>Journal of agricultural and food chemistry, 2006-09, Vol.54 (19), p.7041-7046</ispartof><rights>Copyright © 2006 American Chemical Society</rights><rights>2006 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a405t-911e08946379f346c42068ae4cc60a0f4493b02c1ce890c1895af679eb8638333</citedby><cites>FETCH-LOGICAL-a405t-911e08946379f346c42068ae4cc60a0f4493b02c1ce890c1895af679eb8638333</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jf0606611$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jf0606611$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,780,784,2765,27076,27924,27925,56738,56788</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=18119900$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16968061$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kern, Melanie</creatorcontrib><creatorcontrib>Pahlke, Gudrun</creatorcontrib><creatorcontrib>Ngiewih, Yufanyi</creatorcontrib><creatorcontrib>Marko, Doris</creatorcontrib><title>Modulation of Key Elements of the Wnt Pathway by Apple Polyphenols</title><title>Journal of agricultural and food chemistry</title><addtitle>J. Agric. Food Chem</addtitle><description>Glycogen synthase kinase-3β (GSK3β) is one of the key elements of the Wnt pathway involved in the regulation of β-catenin homeostasis. The inhibition of GSK3β kinase activity might lead to the onset of β-catenin/TCF/LEF-mediated gene transcription, representing a potentially mitogenic stimulus. Apple polyphenols have been shown to mediate several biological effects that might be of interest with respect to chemoprevention. The objective of the study was to elucidate whether apple polyphenols also modulate key elements of the Wnt pathway, an effect that might limit the usefulness of these compounds for the prevention of carcinogenesis. A polyphenol-rich apple juice extract (AE02) was found to effectively inhibit the kinase activity of GSK3β, immunoprecipitated from HT29 cells. Treatment of HT29 cells with AE02 for 24 h resulted in a concentration-dependent decrease of the cellular GSK3β kinase activity. The inhibition of the kinase activity in HT29 cells was observed at polyphenol concentrations corresponding to the concentration of the constituents in the original apple juice. The apple characteristic dihydrochalcone glycoside phloridzin was found to be inactive up to 500 μM. The free aglycon phloretin as well as the flavonol quercetin effectively inhibited isolated GSK3β, but did not affect the respective kinase activity within HT29 cells. In accordance with the inhibition of GSK3β kinase activity by AE02, treatment of HT29 cells resulted in a significant decrease of phosphorylated β-catenin. However, the total intracellular β-catenin level was also found to be diminished, indicating that the interference of the apple constituents with GSK3β was not associated with a stabilization of β-catenin in HT29 cells. In line with these results, TCF/LEF-mediated gene transcription remained unaffected by treatment with AE02 as shown in a reporter gene approach. We can assume from the results that at consumer-relevant concentrations apple polyphenols do not mediate growth-stimulating effects in HT29 cells via the Wnt pathway. Keywords: Phloretin; phloridzin; quercetin; glycogen synthase kinase-3β; β-catenin; colon carcinoma; HT29</description><subject>apple juice</subject><subject>apples</subject><subject>beta Catenin - metabolism</subject><subject>biochemical pathways</subject><subject>Biological and medical sciences</subject><subject>Blotting, Western</subject><subject>carcinogenesis</subject><subject>colorectal neoplasms</subject><subject>disease prevention</subject><subject>enzyme activity</subject><subject>enzyme inhibitors</subject><subject>Flavonoids - pharmacology</subject><subject>food composition</subject><subject>Food industries</subject><subject>Fruit - chemistry</subject><subject>Fruit and vegetable industries</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>gene expression</subject><subject>Glycogen Synthase Kinase 3 - antagonists & inhibitors</subject><subject>Glycogen Synthase Kinase 3 beta</subject><subject>Homeostasis</subject><subject>HT29 Cells</subject><subject>Humans</subject><subject>Immunosorbent Techniques</subject><subject>Malus - chemistry</subject><subject>Phenols - pharmacology</subject><subject>Polyphenols</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>protein kinases</subject><subject>reporter genes</subject><subject>Transcription, Genetic - drug effects</subject><subject>Wnt pathway</subject><subject>Wnt Proteins - metabolism</subject><issn>0021-8561</issn><issn>1520-5118</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpt0E1PwzAMBuAIgWAMDvwB6IUDh4LdtG5yhGl8CCYmGIJblGUJ2-jaqukE_fcUbdounKzIjxz7ZewE4RIhwqu5AwIixB3WwSSCMEEUu6wDbTMUCeEBO_R-DgAiSWGfHSBJEkDYYTeDYrLMdD0r8qBwwaNtgn5mFzav_d-7ntrgPa-Doa6n37oJxk1wXZaZDYZF1pRTmxeZP2J7TmfeHq9rl73d9ke9-_Dp-e6hd_0U6hiSOpSIFoSMiafS8ZhMHAEJbWNjCDS4OJZ8DJFBY4UEg0Im2lEq7VgQF5zzLrtYzTVV4X1lnSqr2UJXjUJQfzmoTQ6tPV3Zcjle2MlWrg9vwfkaaG905iqdm5nfOoEoJUDrwpWb-dr-bPq6-lKU8jRRo-GrosHjaPgyIPXR-rOVd7pQ-rNqZ769RoAcsF2RBN_-rI1X82JZ5W1o_5zwCwDohoI</recordid><startdate>20060920</startdate><enddate>20060920</enddate><creator>Kern, Melanie</creator><creator>Pahlke, Gudrun</creator><creator>Ngiewih, Yufanyi</creator><creator>Marko, Doris</creator><general>American Chemical Society</general><scope>FBQ</scope><scope>BSCLL</scope><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope></search><sort><creationdate>20060920</creationdate><title>Modulation of Key Elements of the Wnt Pathway by Apple Polyphenols</title><author>Kern, Melanie ; Pahlke, Gudrun ; Ngiewih, Yufanyi ; Marko, Doris</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a405t-911e08946379f346c42068ae4cc60a0f4493b02c1ce890c1895af679eb8638333</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2006</creationdate><topic>apple juice</topic><topic>apples</topic><topic>beta Catenin - metabolism</topic><topic>biochemical pathways</topic><topic>Biological and medical sciences</topic><topic>Blotting, Western</topic><topic>carcinogenesis</topic><topic>colorectal neoplasms</topic><topic>disease prevention</topic><topic>enzyme activity</topic><topic>enzyme inhibitors</topic><topic>Flavonoids - pharmacology</topic><topic>food composition</topic><topic>Food industries</topic><topic>Fruit - chemistry</topic><topic>Fruit and vegetable industries</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>gene expression</topic><topic>Glycogen Synthase Kinase 3 - antagonists & inhibitors</topic><topic>Glycogen Synthase Kinase 3 beta</topic><topic>Homeostasis</topic><topic>HT29 Cells</topic><topic>Humans</topic><topic>Immunosorbent Techniques</topic><topic>Malus - chemistry</topic><topic>Phenols - pharmacology</topic><topic>Polyphenols</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>protein kinases</topic><topic>reporter genes</topic><topic>Transcription, Genetic - drug effects</topic><topic>Wnt pathway</topic><topic>Wnt Proteins - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kern, Melanie</creatorcontrib><creatorcontrib>Pahlke, Gudrun</creatorcontrib><creatorcontrib>Ngiewih, Yufanyi</creatorcontrib><creatorcontrib>Marko, Doris</creatorcontrib><collection>AGRIS</collection><collection>Istex</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><jtitle>Journal of agricultural and food chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kern, Melanie</au><au>Pahlke, Gudrun</au><au>Ngiewih, Yufanyi</au><au>Marko, Doris</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Modulation of Key Elements of the Wnt Pathway by Apple Polyphenols</atitle><jtitle>Journal of agricultural and food chemistry</jtitle><addtitle>J. Agric. Food Chem</addtitle><date>2006-09-20</date><risdate>2006</risdate><volume>54</volume><issue>19</issue><spage>7041</spage><epage>7046</epage><pages>7041-7046</pages><issn>0021-8561</issn><eissn>1520-5118</eissn><coden>JAFCAU</coden><abstract>Glycogen synthase kinase-3β (GSK3β) is one of the key elements of the Wnt pathway involved in the regulation of β-catenin homeostasis. The inhibition of GSK3β kinase activity might lead to the onset of β-catenin/TCF/LEF-mediated gene transcription, representing a potentially mitogenic stimulus. Apple polyphenols have been shown to mediate several biological effects that might be of interest with respect to chemoprevention. The objective of the study was to elucidate whether apple polyphenols also modulate key elements of the Wnt pathway, an effect that might limit the usefulness of these compounds for the prevention of carcinogenesis. A polyphenol-rich apple juice extract (AE02) was found to effectively inhibit the kinase activity of GSK3β, immunoprecipitated from HT29 cells. Treatment of HT29 cells with AE02 for 24 h resulted in a concentration-dependent decrease of the cellular GSK3β kinase activity. The inhibition of the kinase activity in HT29 cells was observed at polyphenol concentrations corresponding to the concentration of the constituents in the original apple juice. The apple characteristic dihydrochalcone glycoside phloridzin was found to be inactive up to 500 μM. The free aglycon phloretin as well as the flavonol quercetin effectively inhibited isolated GSK3β, but did not affect the respective kinase activity within HT29 cells. In accordance with the inhibition of GSK3β kinase activity by AE02, treatment of HT29 cells resulted in a significant decrease of phosphorylated β-catenin. However, the total intracellular β-catenin level was also found to be diminished, indicating that the interference of the apple constituents with GSK3β was not associated with a stabilization of β-catenin in HT29 cells. In line with these results, TCF/LEF-mediated gene transcription remained unaffected by treatment with AE02 as shown in a reporter gene approach. We can assume from the results that at consumer-relevant concentrations apple polyphenols do not mediate growth-stimulating effects in HT29 cells via the Wnt pathway. Keywords: Phloretin; phloridzin; quercetin; glycogen synthase kinase-3β; β-catenin; colon carcinoma; HT29</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>16968061</pmid><doi>10.1021/jf0606611</doi><tpages>6</tpages></addata></record> |
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| subjects | apple juice apples beta Catenin - metabolism biochemical pathways Biological and medical sciences Blotting, Western carcinogenesis colorectal neoplasms disease prevention enzyme activity enzyme inhibitors Flavonoids - pharmacology food composition Food industries Fruit - chemistry Fruit and vegetable industries Fundamental and applied biological sciences. Psychology gene expression Glycogen Synthase Kinase 3 - antagonists & inhibitors Glycogen Synthase Kinase 3 beta Homeostasis HT29 Cells Humans Immunosorbent Techniques Malus - chemistry Phenols - pharmacology Polyphenols Protein Kinase Inhibitors - pharmacology protein kinases reporter genes Transcription, Genetic - drug effects Wnt pathway Wnt Proteins - metabolism |
| title | Modulation of Key Elements of the Wnt Pathway by Apple Polyphenols |
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