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Conditional Akt activation promotes androgen-independent progression of prostate cancer
Aggressive androgen-independent (also termed as hormone-refractory) prostate cancer is a major clinical obstacle because there is no means to cure. Previous studies have shown that Akt activation is associated with prostate cancer progression from androgen-dependent to androgen-independent stage. Ho...
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Published in: | Carcinogenesis (New York) 2007-03, Vol.28 (3), p.572-583 |
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creator | Li, Benyi Sun, Aijing Youn, Hyewon Hong, Yan Terranova, Paul F. Thrasher, J.Brantley Xu, Pingyi Spencer, David |
description | Aggressive androgen-independent (also termed as hormone-refractory) prostate cancer is a major clinical obstacle because there is no means to cure. Previous studies have shown that Akt activation is associated with prostate cancer progression from androgen-dependent to androgen-independent stage. However, its causative role in this process has not been established. One of the major limitations is the lack of a well-controlled inducible system to study Akt involvement. Recently, we developed a novel inducible Akt (iAKT) system based on a chemically induced dimerization (CID) approach. This system allows for conditional activation of Akt in a physiological setting. Utilizing this iAKT system, we found that Akt activation prevented cell death after serum withdrawal and promoted cell proliferation in the absence of androgen in vitro in human prostate cancer LNCaP cells, which should stop growing after androgen withdrawal or even die after serum starvation. The iAKT-induced death protection and growth promotion were further demonstrated in vivo using a transgenic mouse model that expresses the iAKT system conditionally in the prostate epithelium. Most importantly, in a mouse xenograft model derived from LNCaP cells, iAKT activation promoted tumor growth in castrated animals by enhancing cell proliferation and inhibiting apoptosis. Taken together, our data suggest that Akt activation is playing a causative role in androgen-independent progression of prostate cancer. This study provides a significant relevance of Akt-targeted therapy for hormone-refractory prostate cancers. |
doi_str_mv | 10.1093/carcin/bgl193 |
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Previous studies have shown that Akt activation is associated with prostate cancer progression from androgen-dependent to androgen-independent stage. However, its causative role in this process has not been established. One of the major limitations is the lack of a well-controlled inducible system to study Akt involvement. Recently, we developed a novel inducible Akt (iAKT) system based on a chemically induced dimerization (CID) approach. This system allows for conditional activation of Akt in a physiological setting. Utilizing this iAKT system, we found that Akt activation prevented cell death after serum withdrawal and promoted cell proliferation in the absence of androgen in vitro in human prostate cancer LNCaP cells, which should stop growing after androgen withdrawal or even die after serum starvation. The iAKT-induced death protection and growth promotion were further demonstrated in vivo using a transgenic mouse model that expresses the iAKT system conditionally in the prostate epithelium. Most importantly, in a mouse xenograft model derived from LNCaP cells, iAKT activation promoted tumor growth in castrated animals by enhancing cell proliferation and inhibiting apoptosis. Taken together, our data suggest that Akt activation is playing a causative role in androgen-independent progression of prostate cancer. This study provides a significant relevance of Akt-targeted therapy for hormone-refractory prostate cancers.</description><identifier>ISSN: 0143-3334</identifier><identifier>EISSN: 1460-2180</identifier><identifier>DOI: 10.1093/carcin/bgl193</identifier><identifier>PMID: 17032658</identifier><identifier>CODEN: CRNGDP</identifier><language>eng</language><publisher>Oxford: Oxford University Press</publisher><subject>Androgens - physiology ; Animals ; Biological and medical sciences ; Carcinogenesis, carcinogens and anticarcinogens ; Cell Division ; Cell Line, Tumor ; Cell Survival ; Culture Media ; Dimerization ; Disease Progression ; Enzyme Activation ; Gynecology. Andrology. Obstetrics ; Humans ; Male ; Male genital diseases ; Medical sciences ; Mice ; Mice, Nude ; Nephrology. Urinary tract diseases ; Prostatic Neoplasms - enzymology ; Prostatic Neoplasms - pathology ; Proto-Oncogene Proteins c-akt - metabolism ; Transplantation, Heterologous ; Tumors ; Tumors of the urinary system ; Urinary tract. Prostate gland</subject><ispartof>Carcinogenesis (New York), 2007-03, Vol.28 (3), p.572-583</ispartof><rights>2006 The Author 2007</rights><rights>2007 INIST-CNRS</rights><rights>Copyright Oxford University Press(England) Mar 2007</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c516t-cb1186a34f5b629e17bb9ec7c71ba5d755d27b745a4648b8d93b6d2de21fba463</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=18669191$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/17032658$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Li, Benyi</creatorcontrib><creatorcontrib>Sun, Aijing</creatorcontrib><creatorcontrib>Youn, Hyewon</creatorcontrib><creatorcontrib>Hong, Yan</creatorcontrib><creatorcontrib>Terranova, Paul F.</creatorcontrib><creatorcontrib>Thrasher, J.Brantley</creatorcontrib><creatorcontrib>Xu, Pingyi</creatorcontrib><creatorcontrib>Spencer, David</creatorcontrib><title>Conditional Akt activation promotes androgen-independent progression of prostate cancer</title><title>Carcinogenesis (New York)</title><addtitle>Carcinogenesis</addtitle><description>Aggressive androgen-independent (also termed as hormone-refractory) prostate cancer is a major clinical obstacle because there is no means to cure. Previous studies have shown that Akt activation is associated with prostate cancer progression from androgen-dependent to androgen-independent stage. However, its causative role in this process has not been established. One of the major limitations is the lack of a well-controlled inducible system to study Akt involvement. Recently, we developed a novel inducible Akt (iAKT) system based on a chemically induced dimerization (CID) approach. This system allows for conditional activation of Akt in a physiological setting. Utilizing this iAKT system, we found that Akt activation prevented cell death after serum withdrawal and promoted cell proliferation in the absence of androgen in vitro in human prostate cancer LNCaP cells, which should stop growing after androgen withdrawal or even die after serum starvation. The iAKT-induced death protection and growth promotion were further demonstrated in vivo using a transgenic mouse model that expresses the iAKT system conditionally in the prostate epithelium. Most importantly, in a mouse xenograft model derived from LNCaP cells, iAKT activation promoted tumor growth in castrated animals by enhancing cell proliferation and inhibiting apoptosis. Taken together, our data suggest that Akt activation is playing a causative role in androgen-independent progression of prostate cancer. This study provides a significant relevance of Akt-targeted therapy for hormone-refractory prostate cancers.</description><subject>Androgens - physiology</subject><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Carcinogenesis, carcinogens and anticarcinogens</subject><subject>Cell Division</subject><subject>Cell Line, Tumor</subject><subject>Cell Survival</subject><subject>Culture Media</subject><subject>Dimerization</subject><subject>Disease Progression</subject><subject>Enzyme Activation</subject><subject>Gynecology. Andrology. Obstetrics</subject><subject>Humans</subject><subject>Male</subject><subject>Male genital diseases</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Nude</subject><subject>Nephrology. Urinary tract diseases</subject><subject>Prostatic Neoplasms - enzymology</subject><subject>Prostatic Neoplasms - pathology</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>Transplantation, Heterologous</subject><subject>Tumors</subject><subject>Tumors of the urinary system</subject><subject>Urinary tract. Prostate gland</subject><issn>0143-3334</issn><issn>1460-2180</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2007</creationdate><recordtype>article</recordtype><recordid>eNqF0M9rFDEUB_AgFrutHr3KIFi8jM1LMsnkWBa1wqIIiuIl5NcsaWdn1iRT6n9vhhks9OIlIS8f8vK-CL0E_A6wpJdWRxuGS7PvQdInaAOM45pAi5-iDQZGa0opO0VnKd1gDJw28hk6BYEp4U27QT-24-BCDuOg--rqNlfa5nCn50J1jONhzD5VenBx3PuhDoPzR1-WIc-3--hTmuXYzceUdfaV1YP18Tk66XSf_It1P0ffP7z_tr2ud18-ftpe7WrbAM-1NQAt15R1jeFEehDGSG-FFWB040TTOCKMYI1mnLWmdZIa7ojzBDpTavQcXSzvlv6_J5-yOoRkfd_rwY9TUiA5FmXaAl8_gjfjFMvUSZGSHANCRUH1gmyZJkXfqWMMBx3_KMBqjlstcasl7uJfrY9O5uDdg17zLeDNCnSyuu9iCSekB9dyLkFCcW8XN07H__Zc_xhS9vf_sI63igsqGnX985eijOw-U4HVV_oX7-6n0Q</recordid><startdate>20070301</startdate><enddate>20070301</enddate><creator>Li, Benyi</creator><creator>Sun, Aijing</creator><creator>Youn, Hyewon</creator><creator>Hong, Yan</creator><creator>Terranova, Paul F.</creator><creator>Thrasher, J.Brantley</creator><creator>Xu, Pingyi</creator><creator>Spencer, David</creator><general>Oxford University Press</general><general>Oxford Publishing Limited (England)</general><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><scope>7T5</scope><scope>7TM</scope><scope>7TO</scope><scope>7U7</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>P64</scope><scope>RC3</scope></search><sort><creationdate>20070301</creationdate><title>Conditional Akt activation promotes androgen-independent progression of prostate cancer</title><author>Li, Benyi ; Sun, Aijing ; Youn, Hyewon ; Hong, Yan ; Terranova, Paul F. ; Thrasher, J.Brantley ; Xu, Pingyi ; Spencer, David</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c516t-cb1186a34f5b629e17bb9ec7c71ba5d755d27b745a4648b8d93b6d2de21fba463</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2007</creationdate><topic>Androgens - physiology</topic><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Carcinogenesis, carcinogens and anticarcinogens</topic><topic>Cell Division</topic><topic>Cell Line, Tumor</topic><topic>Cell Survival</topic><topic>Culture Media</topic><topic>Dimerization</topic><topic>Disease Progression</topic><topic>Enzyme Activation</topic><topic>Gynecology. Andrology. Obstetrics</topic><topic>Humans</topic><topic>Male</topic><topic>Male genital diseases</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, Nude</topic><topic>Nephrology. Urinary tract diseases</topic><topic>Prostatic Neoplasms - enzymology</topic><topic>Prostatic Neoplasms - pathology</topic><topic>Proto-Oncogene Proteins c-akt - metabolism</topic><topic>Transplantation, Heterologous</topic><topic>Tumors</topic><topic>Tumors of the urinary system</topic><topic>Urinary tract. Prostate gland</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Li, Benyi</creatorcontrib><creatorcontrib>Sun, Aijing</creatorcontrib><creatorcontrib>Youn, Hyewon</creatorcontrib><creatorcontrib>Hong, Yan</creatorcontrib><creatorcontrib>Terranova, Paul F.</creatorcontrib><creatorcontrib>Thrasher, J.Brantley</creatorcontrib><creatorcontrib>Xu, Pingyi</creatorcontrib><creatorcontrib>Spencer, David</creatorcontrib><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><collection>Immunology Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><jtitle>Carcinogenesis (New York)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Li, Benyi</au><au>Sun, Aijing</au><au>Youn, Hyewon</au><au>Hong, Yan</au><au>Terranova, Paul F.</au><au>Thrasher, J.Brantley</au><au>Xu, Pingyi</au><au>Spencer, David</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Conditional Akt activation promotes androgen-independent progression of prostate cancer</atitle><jtitle>Carcinogenesis (New York)</jtitle><addtitle>Carcinogenesis</addtitle><date>2007-03-01</date><risdate>2007</risdate><volume>28</volume><issue>3</issue><spage>572</spage><epage>583</epage><pages>572-583</pages><issn>0143-3334</issn><eissn>1460-2180</eissn><coden>CRNGDP</coden><abstract>Aggressive androgen-independent (also termed as hormone-refractory) prostate cancer is a major clinical obstacle because there is no means to cure. Previous studies have shown that Akt activation is associated with prostate cancer progression from androgen-dependent to androgen-independent stage. However, its causative role in this process has not been established. One of the major limitations is the lack of a well-controlled inducible system to study Akt involvement. Recently, we developed a novel inducible Akt (iAKT) system based on a chemically induced dimerization (CID) approach. This system allows for conditional activation of Akt in a physiological setting. Utilizing this iAKT system, we found that Akt activation prevented cell death after serum withdrawal and promoted cell proliferation in the absence of androgen in vitro in human prostate cancer LNCaP cells, which should stop growing after androgen withdrawal or even die after serum starvation. The iAKT-induced death protection and growth promotion were further demonstrated in vivo using a transgenic mouse model that expresses the iAKT system conditionally in the prostate epithelium. Most importantly, in a mouse xenograft model derived from LNCaP cells, iAKT activation promoted tumor growth in castrated animals by enhancing cell proliferation and inhibiting apoptosis. Taken together, our data suggest that Akt activation is playing a causative role in androgen-independent progression of prostate cancer. This study provides a significant relevance of Akt-targeted therapy for hormone-refractory prostate cancers.</abstract><cop>Oxford</cop><pub>Oxford University Press</pub><pmid>17032658</pmid><doi>10.1093/carcin/bgl193</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Androgens - physiology Animals Biological and medical sciences Carcinogenesis, carcinogens and anticarcinogens Cell Division Cell Line, Tumor Cell Survival Culture Media Dimerization Disease Progression Enzyme Activation Gynecology. Andrology. Obstetrics Humans Male Male genital diseases Medical sciences Mice Mice, Nude Nephrology. Urinary tract diseases Prostatic Neoplasms - enzymology Prostatic Neoplasms - pathology Proto-Oncogene Proteins c-akt - metabolism Transplantation, Heterologous Tumors Tumors of the urinary system Urinary tract. Prostate gland |
title | Conditional Akt activation promotes androgen-independent progression of prostate cancer |
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