Dasatinib inhibits site-specific tyrosine phosphorylation of androgen receptor by Ack1 and Src kinases
Activation of androgen receptor (AR) may have a role in the development of castration-resistant prostate cancer. Two intracellular tyrosine kinases, Ack1 (activated cdc42-associated kinase) and Src, phosphorylate and enhance AR activity and promote prostate xenograft tumor growth in castrated animal...
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| Veröffentlicht in: | Oncogene 2010-06, Vol.29 (22), p.3208-3216 |
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| description | Activation of androgen receptor (AR) may have a role in the development of castration-resistant prostate cancer. Two intracellular tyrosine kinases, Ack1 (activated cdc42-associated kinase) and Src, phosphorylate and enhance AR activity and promote prostate xenograft tumor growth in castrated animals. However, the upstream signals that activate these kinases and lead to AR activation are incompletely characterized. In this study, we investigated AR phosphorylation in response to non-androgen ligand stimulation using phospho-specific antibodies. Treatment of LNCaP and LAPC-4 cells with epidermal growth factor (EGF), heregulin, Gas6 (ligand binding to the Mer receptor tyrosine kinase and activating Ack1 downstream), interleukin (IL)-6 or bombesin stimulated cell proliferation in the absence of androgen. Treatment of LNCaP and LAPC-4 cells with EGF, heregulin or Gas6 induced AR phosphorylation at Tyr-267, whereas IL-6 or bombesin treatment did not. AR phosphorylation at Tyr-534 was induced by treatment with EGF, IL-6 or bombesin, but not by heregulin or Gas6. Small interfering RNA-mediated knockdown of Ack1 or Src showed that Ack1 mediates heregulin- and Gas6-induced AR Tyr-267 phosphorylation, whereas Src mediates Tyr-534 phosphorylation induced by EGF, IL-6 and bombesin. Dasatinib, a Src inhibitor, blocked EGF-induced Tyr-534 phosphorylation. In addition, we showed that dasatinib also inhibited Ack1 kinase. Dasatinib inhibited heregulin-induced Ack1 kinase activity and AR Tyr-267 phosphorylation. In addition, dasatinib inhibited heregulin-induced AR-dependent reporter activity. Dasatinib also inhibited heregulin-induced expression of endogenous AR target genes. Dasatinib inhibited Ack1-dependent colony formation and prostate xenograft tumor growth in castrated mice. Interestingly, Ack1 or Src knockdown or dasatinib did not inhibit EGF-induced AR Tyr-267 phosphorylation or EGF-stimulated AR activity, suggesting the existence of an additional tyrosine kinase that phosphorylates AR at Tyr-267. These data suggest that specific tyrosine kinases phosphorylate AR at distinct sites and that dasatinib may exert antitumor activity in prostate cancer through inhibition of Ack1. |
| doi_str_mv | 10.1038/onc.2010.103 |
| format | Article |
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Two intracellular tyrosine kinases, Ack1 (activated cdc42-associated kinase) and Src, phosphorylate and enhance AR activity and promote prostate xenograft tumor growth in castrated animals. However, the upstream signals that activate these kinases and lead to AR activation are incompletely characterized. In this study, we investigated AR phosphorylation in response to non-androgen ligand stimulation using phospho-specific antibodies. Treatment of LNCaP and LAPC-4 cells with epidermal growth factor (EGF), heregulin, Gas6 (ligand binding to the Mer receptor tyrosine kinase and activating Ack1 downstream), interleukin (IL)-6 or bombesin stimulated cell proliferation in the absence of androgen. Treatment of LNCaP and LAPC-4 cells with EGF, heregulin or Gas6 induced AR phosphorylation at Tyr-267, whereas IL-6 or bombesin treatment did not. AR phosphorylation at Tyr-534 was induced by treatment with EGF, IL-6 or bombesin, but not by heregulin or Gas6. Small interfering RNA-mediated knockdown of Ack1 or Src showed that Ack1 mediates heregulin- and Gas6-induced AR Tyr-267 phosphorylation, whereas Src mediates Tyr-534 phosphorylation induced by EGF, IL-6 and bombesin. Dasatinib, a Src inhibitor, blocked EGF-induced Tyr-534 phosphorylation. In addition, we showed that dasatinib also inhibited Ack1 kinase. Dasatinib inhibited heregulin-induced Ack1 kinase activity and AR Tyr-267 phosphorylation. In addition, dasatinib inhibited heregulin-induced AR-dependent reporter activity. Dasatinib also inhibited heregulin-induced expression of endogenous AR target genes. Dasatinib inhibited Ack1-dependent colony formation and prostate xenograft tumor growth in castrated mice. Interestingly, Ack1 or Src knockdown or dasatinib did not inhibit EGF-induced AR Tyr-267 phosphorylation or EGF-stimulated AR activity, suggesting the existence of an additional tyrosine kinase that phosphorylates AR at Tyr-267. These data suggest that specific tyrosine kinases phosphorylate AR at distinct sites and that dasatinib may exert antitumor activity in prostate cancer through inhibition of Ack1.</description><identifier>ISSN: 0950-9232</identifier><identifier>EISSN: 1476-5594</identifier><identifier>DOI: 10.1038/onc.2010.103</identifier><identifier>PMID: 20383201</identifier><identifier>CODEN: ONCNES</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>631/92/436/2387 ; 692/699/67/589/466 ; Androgen Receptor Antagonists ; Androgen receptors ; Androgens ; Animals ; Antitumor activity ; Apoptosis ; Biological and medical sciences ; Bombesin ; Castration ; Cdc42 protein ; Cell Biology ; Cell Growth Processes - drug effects ; Cell Line, Tumor ; Cell physiology ; Cell proliferation ; Cell receptors ; Cell structures and functions ; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes ; Cellular biology ; Cercopithecus aethiops ; COS Cells ; Dasatinib ; Dosage and administration ; Drug therapy ; Epidermal growth factor ; Fundamental and applied biological sciences. Psychology ; Genetics ; Heregulin ; Hormone receptors ; Human Genetics ; Humans ; Immunoblotting ; Interleukin 6 ; Internal Medicine ; Kinases ; Ligands ; Male ; Medical sciences ; Medicine ; Medicine & Public Health ; Mice ; Miscellaneous ; Molecular and cellular biology ; Nephrology. Urinary tract diseases ; Oncology ; original-article ; Phosphorylation ; Phosphorylation - drug effects ; Physiological aspects ; Prostate cancer ; Prostatic Neoplasms - drug therapy ; Prostatic Neoplasms - genetics ; Prostatic Neoplasms - metabolism ; Prostatic Neoplasms - pathology ; Protein Kinase Inhibitors - pharmacology ; Protein kinases ; Protein-tyrosine kinase receptors ; Protein-Tyrosine Kinases - antagonists & inhibitors ; Protein-Tyrosine Kinases - genetics ; Protein-Tyrosine Kinases - metabolism ; Pyrimidines - pharmacology ; Receptors, Androgen - genetics ; Receptors, Androgen - metabolism ; Signal Transduction ; siRNA ; src-Family Kinases - antagonists & inhibitors ; src-Family Kinases - genetics ; src-Family Kinases - metabolism ; Thiazoles - pharmacology ; Transfection ; Tumors ; Tumors of the urinary system ; Urinary tract. Prostate gland ; Xenograft Model Antitumor Assays ; Xenografts</subject><ispartof>Oncogene, 2010-06, Vol.29 (22), p.3208-3216</ispartof><rights>Macmillan Publishers Limited 2010</rights><rights>2015 INIST-CNRS</rights><rights>COPYRIGHT 2010 Nature Publishing Group</rights><rights>Macmillan Publishers Limited 2010.</rights><rights>Copyright Nature Publishing Group Jun 3, 2010</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c671t-e8f6f04fea53d223761551ee012edd386935589c593249f64bc78d6a7554a9f93</citedby><cites>FETCH-LOGICAL-c671t-e8f6f04fea53d223761551ee012edd386935589c593249f64bc78d6a7554a9f93</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/onc.2010.103$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/onc.2010.103$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>230,314,776,780,881,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=22895964$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20383201$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Liu, Y</creatorcontrib><creatorcontrib>Karaca, M</creatorcontrib><creatorcontrib>Zhang, Z</creatorcontrib><creatorcontrib>Gioeli, D</creatorcontrib><creatorcontrib>Earp, H S</creatorcontrib><creatorcontrib>Whang, Y E</creatorcontrib><title>Dasatinib inhibits site-specific tyrosine phosphorylation of androgen receptor by Ack1 and Src kinases</title><title>Oncogene</title><addtitle>Oncogene</addtitle><addtitle>Oncogene</addtitle><description>Activation of androgen receptor (AR) may have a role in the development of castration-resistant prostate cancer. Two intracellular tyrosine kinases, Ack1 (activated cdc42-associated kinase) and Src, phosphorylate and enhance AR activity and promote prostate xenograft tumor growth in castrated animals. However, the upstream signals that activate these kinases and lead to AR activation are incompletely characterized. In this study, we investigated AR phosphorylation in response to non-androgen ligand stimulation using phospho-specific antibodies. Treatment of LNCaP and LAPC-4 cells with epidermal growth factor (EGF), heregulin, Gas6 (ligand binding to the Mer receptor tyrosine kinase and activating Ack1 downstream), interleukin (IL)-6 or bombesin stimulated cell proliferation in the absence of androgen. Treatment of LNCaP and LAPC-4 cells with EGF, heregulin or Gas6 induced AR phosphorylation at Tyr-267, whereas IL-6 or bombesin treatment did not. AR phosphorylation at Tyr-534 was induced by treatment with EGF, IL-6 or bombesin, but not by heregulin or Gas6. Small interfering RNA-mediated knockdown of Ack1 or Src showed that Ack1 mediates heregulin- and Gas6-induced AR Tyr-267 phosphorylation, whereas Src mediates Tyr-534 phosphorylation induced by EGF, IL-6 and bombesin. Dasatinib, a Src inhibitor, blocked EGF-induced Tyr-534 phosphorylation. In addition, we showed that dasatinib also inhibited Ack1 kinase. Dasatinib inhibited heregulin-induced Ack1 kinase activity and AR Tyr-267 phosphorylation. In addition, dasatinib inhibited heregulin-induced AR-dependent reporter activity. Dasatinib also inhibited heregulin-induced expression of endogenous AR target genes. Dasatinib inhibited Ack1-dependent colony formation and prostate xenograft tumor growth in castrated mice. Interestingly, Ack1 or Src knockdown or dasatinib did not inhibit EGF-induced AR Tyr-267 phosphorylation or EGF-stimulated AR activity, suggesting the existence of an additional tyrosine kinase that phosphorylates AR at Tyr-267. These data suggest that specific tyrosine kinases phosphorylate AR at distinct sites and that dasatinib may exert antitumor activity in prostate cancer through inhibition of Ack1.</description><subject>631/92/436/2387</subject><subject>692/699/67/589/466</subject><subject>Androgen Receptor Antagonists</subject><subject>Androgen receptors</subject><subject>Androgens</subject><subject>Animals</subject><subject>Antitumor activity</subject><subject>Apoptosis</subject><subject>Biological and medical sciences</subject><subject>Bombesin</subject><subject>Castration</subject><subject>Cdc42 protein</subject><subject>Cell Biology</subject><subject>Cell Growth Processes - drug effects</subject><subject>Cell Line, Tumor</subject><subject>Cell physiology</subject><subject>Cell proliferation</subject><subject>Cell receptors</subject><subject>Cell structures and functions</subject><subject>Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes</subject><subject>Cellular biology</subject><subject>Cercopithecus aethiops</subject><subject>COS Cells</subject><subject>Dasatinib</subject><subject>Dosage and administration</subject><subject>Drug therapy</subject><subject>Epidermal growth factor</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Genetics</subject><subject>Heregulin</subject><subject>Hormone receptors</subject><subject>Human Genetics</subject><subject>Humans</subject><subject>Immunoblotting</subject><subject>Interleukin 6</subject><subject>Internal Medicine</subject><subject>Kinases</subject><subject>Ligands</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Mice</subject><subject>Miscellaneous</subject><subject>Molecular and cellular biology</subject><subject>Nephrology. Urinary tract diseases</subject><subject>Oncology</subject><subject>original-article</subject><subject>Phosphorylation</subject><subject>Phosphorylation - drug effects</subject><subject>Physiological aspects</subject><subject>Prostate cancer</subject><subject>Prostatic Neoplasms - drug therapy</subject><subject>Prostatic Neoplasms - genetics</subject><subject>Prostatic Neoplasms - metabolism</subject><subject>Prostatic Neoplasms - pathology</subject><subject>Protein Kinase Inhibitors - pharmacology</subject><subject>Protein kinases</subject><subject>Protein-tyrosine kinase receptors</subject><subject>Protein-Tyrosine Kinases - antagonists & inhibitors</subject><subject>Protein-Tyrosine Kinases - genetics</subject><subject>Protein-Tyrosine Kinases - metabolism</subject><subject>Pyrimidines - pharmacology</subject><subject>Receptors, Androgen - genetics</subject><subject>Receptors, Androgen - metabolism</subject><subject>Signal Transduction</subject><subject>siRNA</subject><subject>src-Family Kinases - antagonists & inhibitors</subject><subject>src-Family Kinases - genetics</subject><subject>src-Family Kinases - metabolism</subject><subject>Thiazoles - pharmacology</subject><subject>Transfection</subject><subject>Tumors</subject><subject>Tumors of the urinary system</subject><subject>Urinary tract. Prostate gland</subject><subject>Xenograft Model Antitumor Assays</subject><subject>Xenografts</subject><issn>0950-9232</issn><issn>1476-5594</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNqFkl2LEzEUhgdR3Lp657UERbxxar4nuRHK-gkLXqjXIc2ctNmdJjWZCv33ZmjturIiIYST87zvISenaZ4SPCeYqTcpujnFh-heMyO8k60Qmt9vZlgL3GrK6FnzqJQrjHGnMX3YnNEqZFU0a_w7W-wYYliiENdhGcaCShihLVtwwQeHxn1OJURA23Uqdef9UAUpouSRjX1OK4gog4PtmDJa7tHCXZMpg75mh65DtAXK4-aBt0OBJ8fzvPn-4f23i0_t5ZePny8Wl62THRlbUF56zD1YwXpKWSeJEAQAEwp9z5TUTAilndCMcu0lX7pO9dJ2QnCrvWbnzduD73a33EDvII7ZDmabw8bmvUk2mNuZGNZmlX4aqhSWYjJ4dTTI6ccOymg2oTgYBhsh7YrpuMSESCr_TzJGmMJ48nz-F3mVdjnWPhgmOqw4IRP04l8QlZxw3JHqeKJWdgATok_1FW4qbBaUKoF1pyav-R1UXT1sgksRfKj3twSvDwJX_7pk8KeOEWymKTN1ysw0ZVNU8Wd_dvkE_x6rCrw8ArY4O_hsowvlhqNKCy155doDV2oqriDfPPrOwr8A5UnnQg</recordid><startdate>20100603</startdate><enddate>20100603</enddate><creator>Liu, Y</creator><creator>Karaca, M</creator><creator>Zhang, Z</creator><creator>Gioeli, D</creator><creator>Earp, H S</creator><creator>Whang, Y E</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</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>3V.</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>M7P</scope><scope>MBDVC</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope><scope>RC3</scope><scope>PRINS</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20100603</creationdate><title>Dasatinib inhibits site-specific tyrosine phosphorylation of androgen receptor by Ack1 and Src kinases</title><author>Liu, Y ; Karaca, M ; Zhang, Z ; Gioeli, D ; Earp, H S ; Whang, Y E</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c671t-e8f6f04fea53d223761551ee012edd386935589c593249f64bc78d6a7554a9f93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>631/92/436/2387</topic><topic>692/699/67/589/466</topic><topic>Androgen Receptor Antagonists</topic><topic>Androgen receptors</topic><topic>Androgens</topic><topic>Animals</topic><topic>Antitumor activity</topic><topic>Apoptosis</topic><topic>Biological and medical sciences</topic><topic>Bombesin</topic><topic>Castration</topic><topic>Cdc42 protein</topic><topic>Cell Biology</topic><topic>Cell Growth Processes - drug effects</topic><topic>Cell Line, Tumor</topic><topic>Cell physiology</topic><topic>Cell proliferation</topic><topic>Cell receptors</topic><topic>Cell structures and functions</topic><topic>Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes</topic><topic>Cellular biology</topic><topic>Cercopithecus aethiops</topic><topic>COS Cells</topic><topic>Dasatinib</topic><topic>Dosage and administration</topic><topic>Drug therapy</topic><topic>Epidermal growth factor</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Genetics</topic><topic>Heregulin</topic><topic>Hormone receptors</topic><topic>Human Genetics</topic><topic>Humans</topic><topic>Immunoblotting</topic><topic>Interleukin 6</topic><topic>Internal Medicine</topic><topic>Kinases</topic><topic>Ligands</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Mice</topic><topic>Miscellaneous</topic><topic>Molecular and cellular biology</topic><topic>Nephrology. Urinary tract diseases</topic><topic>Oncology</topic><topic>original-article</topic><topic>Phosphorylation</topic><topic>Phosphorylation - drug effects</topic><topic>Physiological aspects</topic><topic>Prostate cancer</topic><topic>Prostatic Neoplasms - drug therapy</topic><topic>Prostatic Neoplasms - genetics</topic><topic>Prostatic Neoplasms - metabolism</topic><topic>Prostatic Neoplasms - pathology</topic><topic>Protein Kinase Inhibitors - pharmacology</topic><topic>Protein kinases</topic><topic>Protein-tyrosine kinase receptors</topic><topic>Protein-Tyrosine Kinases - antagonists & inhibitors</topic><topic>Protein-Tyrosine Kinases - genetics</topic><topic>Protein-Tyrosine Kinases - metabolism</topic><topic>Pyrimidines - pharmacology</topic><topic>Receptors, Androgen - genetics</topic><topic>Receptors, Androgen - metabolism</topic><topic>Signal Transduction</topic><topic>siRNA</topic><topic>src-Family Kinases - antagonists & inhibitors</topic><topic>src-Family Kinases - genetics</topic><topic>src-Family Kinases - metabolism</topic><topic>Thiazoles - pharmacology</topic><topic>Transfection</topic><topic>Tumors</topic><topic>Tumors of the urinary system</topic><topic>Urinary tract. Prostate gland</topic><topic>Xenograft Model Antitumor Assays</topic><topic>Xenografts</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Liu, Y</creatorcontrib><creatorcontrib>Karaca, M</creatorcontrib><creatorcontrib>Zhang, Z</creatorcontrib><creatorcontrib>Gioeli, D</creatorcontrib><creatorcontrib>Earp, H S</creatorcontrib><creatorcontrib>Whang, Y E</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>ProQuest Central (Corporate)</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Research Library</collection><collection>Biological Science Database</collection><collection>Research Library (Corporate)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central Basic</collection><collection>Genetics Abstracts</collection><collection>ProQuest Central China</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Oncogene</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Liu, Y</au><au>Karaca, M</au><au>Zhang, Z</au><au>Gioeli, D</au><au>Earp, H S</au><au>Whang, Y E</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Dasatinib inhibits site-specific tyrosine phosphorylation of androgen receptor by Ack1 and Src kinases</atitle><jtitle>Oncogene</jtitle><stitle>Oncogene</stitle><addtitle>Oncogene</addtitle><date>2010-06-03</date><risdate>2010</risdate><volume>29</volume><issue>22</issue><spage>3208</spage><epage>3216</epage><pages>3208-3216</pages><issn>0950-9232</issn><eissn>1476-5594</eissn><coden>ONCNES</coden><abstract>Activation of androgen receptor (AR) may have a role in the development of castration-resistant prostate cancer. Two intracellular tyrosine kinases, Ack1 (activated cdc42-associated kinase) and Src, phosphorylate and enhance AR activity and promote prostate xenograft tumor growth in castrated animals. However, the upstream signals that activate these kinases and lead to AR activation are incompletely characterized. In this study, we investigated AR phosphorylation in response to non-androgen ligand stimulation using phospho-specific antibodies. Treatment of LNCaP and LAPC-4 cells with epidermal growth factor (EGF), heregulin, Gas6 (ligand binding to the Mer receptor tyrosine kinase and activating Ack1 downstream), interleukin (IL)-6 or bombesin stimulated cell proliferation in the absence of androgen. Treatment of LNCaP and LAPC-4 cells with EGF, heregulin or Gas6 induced AR phosphorylation at Tyr-267, whereas IL-6 or bombesin treatment did not. AR phosphorylation at Tyr-534 was induced by treatment with EGF, IL-6 or bombesin, but not by heregulin or Gas6. Small interfering RNA-mediated knockdown of Ack1 or Src showed that Ack1 mediates heregulin- and Gas6-induced AR Tyr-267 phosphorylation, whereas Src mediates Tyr-534 phosphorylation induced by EGF, IL-6 and bombesin. Dasatinib, a Src inhibitor, blocked EGF-induced Tyr-534 phosphorylation. In addition, we showed that dasatinib also inhibited Ack1 kinase. Dasatinib inhibited heregulin-induced Ack1 kinase activity and AR Tyr-267 phosphorylation. In addition, dasatinib inhibited heregulin-induced AR-dependent reporter activity. Dasatinib also inhibited heregulin-induced expression of endogenous AR target genes. Dasatinib inhibited Ack1-dependent colony formation and prostate xenograft tumor growth in castrated mice. Interestingly, Ack1 or Src knockdown or dasatinib did not inhibit EGF-induced AR Tyr-267 phosphorylation or EGF-stimulated AR activity, suggesting the existence of an additional tyrosine kinase that phosphorylates AR at Tyr-267. These data suggest that specific tyrosine kinases phosphorylate AR at distinct sites and that dasatinib may exert antitumor activity in prostate cancer through inhibition of Ack1.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>20383201</pmid><doi>10.1038/onc.2010.103</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_2880659 |
| source | MEDLINE; Springer Nature - Complete Springer Journals; Nature; EZB-FREE-00999 freely available EZB journals |
| subjects | 631/92/436/2387 692/699/67/589/466 Androgen Receptor Antagonists Androgen receptors Androgens Animals Antitumor activity Apoptosis Biological and medical sciences Bombesin Castration Cdc42 protein Cell Biology Cell Growth Processes - drug effects Cell Line, Tumor Cell physiology Cell proliferation Cell receptors Cell structures and functions Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes Cellular biology Cercopithecus aethiops COS Cells Dasatinib Dosage and administration Drug therapy Epidermal growth factor Fundamental and applied biological sciences. Psychology Genetics Heregulin Hormone receptors Human Genetics Humans Immunoblotting Interleukin 6 Internal Medicine Kinases Ligands Male Medical sciences Medicine Medicine & Public Health Mice Miscellaneous Molecular and cellular biology Nephrology. Urinary tract diseases Oncology original-article Phosphorylation Phosphorylation - drug effects Physiological aspects Prostate cancer Prostatic Neoplasms - drug therapy Prostatic Neoplasms - genetics Prostatic Neoplasms - metabolism Prostatic Neoplasms - pathology Protein Kinase Inhibitors - pharmacology Protein kinases Protein-tyrosine kinase receptors Protein-Tyrosine Kinases - antagonists & inhibitors Protein-Tyrosine Kinases - genetics Protein-Tyrosine Kinases - metabolism Pyrimidines - pharmacology Receptors, Androgen - genetics Receptors, Androgen - metabolism Signal Transduction siRNA src-Family Kinases - antagonists & inhibitors src-Family Kinases - genetics src-Family Kinases - metabolism Thiazoles - pharmacology Transfection Tumors Tumors of the urinary system Urinary tract. Prostate gland Xenograft Model Antitumor Assays Xenografts |
| title | Dasatinib inhibits site-specific tyrosine phosphorylation of androgen receptor by Ack1 and Src kinases |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-01T13%3A01%3A00IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Dasatinib%20inhibits%20site-specific%20tyrosine%20phosphorylation%20of%20androgen%20receptor%20by%20Ack1%20and%20Src%20kinases&rft.jtitle=Oncogene&rft.au=Liu,%20Y&rft.date=2010-06-03&rft.volume=29&rft.issue=22&rft.spage=3208&rft.epage=3216&rft.pages=3208-3216&rft.issn=0950-9232&rft.eissn=1476-5594&rft.coden=ONCNES&rft_id=info:doi/10.1038/onc.2010.103&rft_dat=%3Cgale_pubme%3EA228509789%3C/gale_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2641407173&rft_id=info:pmid/20383201&rft_galeid=A228509789&rfr_iscdi=true |