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Metformin, Independent of AMPK, Induces mTOR Inhibition and Cell-Cycle Arrest through REDD1
Metformin is a widely prescribed antidiabetic drug associated with a reduced risk of cancer. Many studies show that metformin inhibits cancer cell viability through the inhibition of mTOR. We recently showed that antiproliferative action of metformin in prostate cancer cell lines is not mediated by...
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Published in: | Cancer research (Chicago, Ill.) Ill.), 2011-07, Vol.71 (13), p.4366-4372 |
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container_title | Cancer research (Chicago, Ill.) |
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creator | ISAAM BEN SAHRA REGAZZETTI, Claire ROBERT, Guillaume LAURENT, Kathiane LE MARCHAND-BRUSTEL, Yannick AUBERGER, Patrick TANTI, Jean-François GIORGETTI-PERALDI, Sophie BOST, Frédéric |
description | Metformin is a widely prescribed antidiabetic drug associated with a reduced risk of cancer. Many studies show that metformin inhibits cancer cell viability through the inhibition of mTOR. We recently showed that antiproliferative action of metformin in prostate cancer cell lines is not mediated by AMP-activated protein kinase (AMPK). We identified REDD1 (also known as DDIT4 and RTP801), a negative regulator of mTOR, as a new molecular target of metformin. We show that metformin increases REDD1 expression in a p53-dependent manner. REDD1 invalidation, using siRNA or REDD1(-/-) cells, abrogates metformin inhibition of mTOR. Importantly, inhibition of REDD1 reverses metformin-induced cell-cycle arrest and significantly protects from the deleterious effects of metformin on cell transformation. Finally, we show the contribution of p53 in mediating metformin action in prostate cancer cells. These results highlight the p53/REDD1 axis as a new molecular target in anticancer therapy in response to metformin treatment. |
doi_str_mv | 10.1158/0008-5472.can-10-1769 |
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Many studies show that metformin inhibits cancer cell viability through the inhibition of mTOR. We recently showed that antiproliferative action of metformin in prostate cancer cell lines is not mediated by AMP-activated protein kinase (AMPK). We identified REDD1 (also known as DDIT4 and RTP801), a negative regulator of mTOR, as a new molecular target of metformin. We show that metformin increases REDD1 expression in a p53-dependent manner. REDD1 invalidation, using siRNA or REDD1(-/-) cells, abrogates metformin inhibition of mTOR. Importantly, inhibition of REDD1 reverses metformin-induced cell-cycle arrest and significantly protects from the deleterious effects of metformin on cell transformation. Finally, we show the contribution of p53 in mediating metformin action in prostate cancer cells. These results highlight the p53/REDD1 axis as a new molecular target in anticancer therapy in response to metformin treatment.</description><identifier>ISSN: 0008-5472</identifier><identifier>EISSN: 1538-7445</identifier><identifier>DOI: 10.1158/0008-5472.can-10-1769</identifier><identifier>PMID: 21540236</identifier><identifier>CODEN: CNREA8</identifier><language>eng</language><publisher>Philadelphia, PA: American Association for Cancer Research</publisher><subject>AMP-Activated Protein Kinases - metabolism ; Animals ; Antineoplastic agents ; Biological and medical sciences ; Cell Cycle - drug effects ; Cell Cycle - physiology ; Cell Line, Tumor ; Cyclin D1 - metabolism ; Humans ; Male ; Medical sciences ; Metformin - pharmacology ; Mice ; Mice, Transgenic ; Pharmacology. Drug treatments ; Prostatic Neoplasms - drug therapy ; Prostatic Neoplasms - genetics ; Prostatic Neoplasms - metabolism ; Prostatic Neoplasms - pathology ; RNA, Messenger - biosynthesis ; RNA, Messenger - genetics ; RNA, Small Interfering - genetics ; TOR Serine-Threonine Kinases - antagonists & inhibitors ; Transcription Factors - biosynthesis ; Transcription Factors - genetics ; Transfection ; Tumor Suppressor Protein p53 - metabolism ; Tumors</subject><ispartof>Cancer research (Chicago, Ill.), 2011-07, Vol.71 (13), p.4366-4372</ispartof><rights>2015 INIST-CNRS</rights><rights>2011 AACR.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c587t-d2451e57644e8c11a2d4d6f80eb268b848532cfebc37c328d15bab0f33fc4dee3</citedby><cites>FETCH-LOGICAL-c587t-d2451e57644e8c11a2d4d6f80eb268b848532cfebc37c328d15bab0f33fc4dee3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,786,790,27957,27958</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=24317320$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21540236$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>ISAAM BEN SAHRA</creatorcontrib><creatorcontrib>REGAZZETTI, Claire</creatorcontrib><creatorcontrib>ROBERT, Guillaume</creatorcontrib><creatorcontrib>LAURENT, Kathiane</creatorcontrib><creatorcontrib>LE MARCHAND-BRUSTEL, Yannick</creatorcontrib><creatorcontrib>AUBERGER, Patrick</creatorcontrib><creatorcontrib>TANTI, Jean-François</creatorcontrib><creatorcontrib>GIORGETTI-PERALDI, Sophie</creatorcontrib><creatorcontrib>BOST, Frédéric</creatorcontrib><title>Metformin, Independent of AMPK, Induces mTOR Inhibition and Cell-Cycle Arrest through REDD1</title><title>Cancer research (Chicago, Ill.)</title><addtitle>Cancer Res</addtitle><description>Metformin is a widely prescribed antidiabetic drug associated with a reduced risk of cancer. Many studies show that metformin inhibits cancer cell viability through the inhibition of mTOR. We recently showed that antiproliferative action of metformin in prostate cancer cell lines is not mediated by AMP-activated protein kinase (AMPK). We identified REDD1 (also known as DDIT4 and RTP801), a negative regulator of mTOR, as a new molecular target of metformin. We show that metformin increases REDD1 expression in a p53-dependent manner. REDD1 invalidation, using siRNA or REDD1(-/-) cells, abrogates metformin inhibition of mTOR. Importantly, inhibition of REDD1 reverses metformin-induced cell-cycle arrest and significantly protects from the deleterious effects of metformin on cell transformation. Finally, we show the contribution of p53 in mediating metformin action in prostate cancer cells. These results highlight the p53/REDD1 axis as a new molecular target in anticancer therapy in response to metformin treatment.</description><subject>AMP-Activated Protein Kinases - metabolism</subject><subject>Animals</subject><subject>Antineoplastic agents</subject><subject>Biological and medical sciences</subject><subject>Cell Cycle - drug effects</subject><subject>Cell Cycle - physiology</subject><subject>Cell Line, Tumor</subject><subject>Cyclin D1 - metabolism</subject><subject>Humans</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Metformin - pharmacology</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>Pharmacology. Drug treatments</subject><subject>Prostatic Neoplasms - drug therapy</subject><subject>Prostatic Neoplasms - genetics</subject><subject>Prostatic Neoplasms - metabolism</subject><subject>Prostatic Neoplasms - pathology</subject><subject>RNA, Messenger - biosynthesis</subject><subject>RNA, Messenger - genetics</subject><subject>RNA, Small Interfering - genetics</subject><subject>TOR Serine-Threonine Kinases - antagonists & inhibitors</subject><subject>Transcription Factors - biosynthesis</subject><subject>Transcription Factors - genetics</subject><subject>Transfection</subject><subject>Tumor Suppressor Protein p53 - metabolism</subject><subject>Tumors</subject><issn>0008-5472</issn><issn>1538-7445</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><recordid>eNqFkclOwzAQhi0EgrI8AsgXxIWA19g9VimboBQhOHGIHGdMg7IUOznw9rhQ4MhlRvPrm0X_IHRIyRmlUp8TQnQihWJn1rQJJQlV6XgDjajkOlFCyE00-mV20G4Ib7GUlMhttMOoFITxdIReZtC7zjdVe4pv2hKWEEPb487hyezh9kscLATcPM0fY7GoiqqvuhabtsQZ1HWSfdga8MR7CD3uF74bXhf48WI6pftoy5k6wME676Hny4un7Dq5m1_dZJO7xEqt-qRkQlKQKhUCtKXUsFKUqdMECpbqQgstObMOCsuV5UyXVBamII5zZ0UJwPfQyffcpe_eh3hG3lTBxttMC90Q8nGqqSKKjP8ltRI60lpHUn6T1ncheHD50leN8R85JfnqAfnK3Hxlbp5N7r_U-IDYd7TeMBQNlL9dP45H4HgNmGBN7bxpbRX-OMGp4ozwTxJrjKc</recordid><startdate>20110701</startdate><enddate>20110701</enddate><creator>ISAAM BEN SAHRA</creator><creator>REGAZZETTI, Claire</creator><creator>ROBERT, Guillaume</creator><creator>LAURENT, Kathiane</creator><creator>LE MARCHAND-BRUSTEL, Yannick</creator><creator>AUBERGER, Patrick</creator><creator>TANTI, Jean-François</creator><creator>GIORGETTI-PERALDI, Sophie</creator><creator>BOST, Frédéric</creator><general>American Association for Cancer Research</general><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><scope>7X8</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope></search><sort><creationdate>20110701</creationdate><title>Metformin, Independent of AMPK, Induces mTOR Inhibition and Cell-Cycle Arrest through REDD1</title><author>ISAAM BEN SAHRA ; REGAZZETTI, Claire ; ROBERT, Guillaume ; LAURENT, Kathiane ; LE MARCHAND-BRUSTEL, Yannick ; AUBERGER, Patrick ; TANTI, Jean-François ; GIORGETTI-PERALDI, Sophie ; BOST, Frédéric</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c587t-d2451e57644e8c11a2d4d6f80eb268b848532cfebc37c328d15bab0f33fc4dee3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>AMP-Activated Protein Kinases - metabolism</topic><topic>Animals</topic><topic>Antineoplastic agents</topic><topic>Biological and medical sciences</topic><topic>Cell Cycle - drug effects</topic><topic>Cell Cycle - physiology</topic><topic>Cell Line, Tumor</topic><topic>Cyclin D1 - metabolism</topic><topic>Humans</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Metformin - pharmacology</topic><topic>Mice</topic><topic>Mice, Transgenic</topic><topic>Pharmacology. Drug treatments</topic><topic>Prostatic Neoplasms - drug therapy</topic><topic>Prostatic Neoplasms - genetics</topic><topic>Prostatic Neoplasms - metabolism</topic><topic>Prostatic Neoplasms - pathology</topic><topic>RNA, Messenger - biosynthesis</topic><topic>RNA, Messenger - genetics</topic><topic>RNA, Small Interfering - genetics</topic><topic>TOR Serine-Threonine Kinases - antagonists & inhibitors</topic><topic>Transcription Factors - biosynthesis</topic><topic>Transcription Factors - genetics</topic><topic>Transfection</topic><topic>Tumor Suppressor Protein p53 - metabolism</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>ISAAM BEN SAHRA</creatorcontrib><creatorcontrib>REGAZZETTI, Claire</creatorcontrib><creatorcontrib>ROBERT, Guillaume</creatorcontrib><creatorcontrib>LAURENT, Kathiane</creatorcontrib><creatorcontrib>LE MARCHAND-BRUSTEL, Yannick</creatorcontrib><creatorcontrib>AUBERGER, Patrick</creatorcontrib><creatorcontrib>TANTI, Jean-François</creatorcontrib><creatorcontrib>GIORGETTI-PERALDI, Sophie</creatorcontrib><creatorcontrib>BOST, Frédéric</creatorcontrib><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><collection>MEDLINE - Academic</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><jtitle>Cancer research (Chicago, Ill.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>ISAAM BEN SAHRA</au><au>REGAZZETTI, Claire</au><au>ROBERT, Guillaume</au><au>LAURENT, Kathiane</au><au>LE MARCHAND-BRUSTEL, Yannick</au><au>AUBERGER, Patrick</au><au>TANTI, Jean-François</au><au>GIORGETTI-PERALDI, Sophie</au><au>BOST, Frédéric</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Metformin, Independent of AMPK, Induces mTOR Inhibition and Cell-Cycle Arrest through REDD1</atitle><jtitle>Cancer research (Chicago, Ill.)</jtitle><addtitle>Cancer Res</addtitle><date>2011-07-01</date><risdate>2011</risdate><volume>71</volume><issue>13</issue><spage>4366</spage><epage>4372</epage><pages>4366-4372</pages><issn>0008-5472</issn><eissn>1538-7445</eissn><coden>CNREA8</coden><notes>ObjectType-Article-1</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-2</notes><notes>content type line 23</notes><notes>ObjectType-Article-2</notes><notes>ObjectType-Feature-1</notes><abstract>Metformin is a widely prescribed antidiabetic drug associated with a reduced risk of cancer. Many studies show that metformin inhibits cancer cell viability through the inhibition of mTOR. We recently showed that antiproliferative action of metformin in prostate cancer cell lines is not mediated by AMP-activated protein kinase (AMPK). We identified REDD1 (also known as DDIT4 and RTP801), a negative regulator of mTOR, as a new molecular target of metformin. We show that metformin increases REDD1 expression in a p53-dependent manner. REDD1 invalidation, using siRNA or REDD1(-/-) cells, abrogates metformin inhibition of mTOR. Importantly, inhibition of REDD1 reverses metformin-induced cell-cycle arrest and significantly protects from the deleterious effects of metformin on cell transformation. Finally, we show the contribution of p53 in mediating metformin action in prostate cancer cells. These results highlight the p53/REDD1 axis as a new molecular target in anticancer therapy in response to metformin treatment.</abstract><cop>Philadelphia, PA</cop><pub>American Association for Cancer Research</pub><pmid>21540236</pmid><doi>10.1158/0008-5472.can-10-1769</doi><tpages>7</tpages><oa>free_for_read</oa></addata></record> |
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subjects | AMP-Activated Protein Kinases - metabolism Animals Antineoplastic agents Biological and medical sciences Cell Cycle - drug effects Cell Cycle - physiology Cell Line, Tumor Cyclin D1 - metabolism Humans Male Medical sciences Metformin - pharmacology Mice Mice, Transgenic Pharmacology. Drug treatments Prostatic Neoplasms - drug therapy Prostatic Neoplasms - genetics Prostatic Neoplasms - metabolism Prostatic Neoplasms - pathology RNA, Messenger - biosynthesis RNA, Messenger - genetics RNA, Small Interfering - genetics TOR Serine-Threonine Kinases - antagonists & inhibitors Transcription Factors - biosynthesis Transcription Factors - genetics Transfection Tumor Suppressor Protein p53 - metabolism Tumors |
title | Metformin, Independent of AMPK, Induces mTOR Inhibition and Cell-Cycle Arrest through REDD1 |
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