VEGF/neuropilin-2 regulation of Bmi-1 and consequent repression of IGF-IR define a novel mechanism of aggressive prostate cancer
We show that the VEGF receptor neuropilin-2 (NRP2) is associated with high-grade, PTEN-null prostate cancer and that its expression in tumor cells is induced by PTEN loss as a consequence of c-Jun activation. VEGF/NRP2 signaling represses insulin-like growth factor-1 receptor (IGF-IR) expression and...
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| Veröffentlicht in: | Cancer discovery 2012-10, Vol.2 (10), p.906-921 |
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| creator | Goel, Hira Lal Chang, Cheng Pursell, Bryan Leav, Irwin Lyle, Stephen Xi, Hualin Simon Hsieh, Chung-Cheng Adisetiyo, Helty Roy-Burman, Pradip Coleman, Ilsa M Nelson, Peter S Vessella, Robert L Davis, Roger J Plymate, Stephen R Mercurio, Arthur M |
| description | We show that the VEGF receptor neuropilin-2 (NRP2) is associated with high-grade, PTEN-null prostate cancer and that its expression in tumor cells is induced by PTEN loss as a consequence of c-Jun activation. VEGF/NRP2 signaling represses insulin-like growth factor-1 receptor (IGF-IR) expression and signaling, and the mechanism involves Bmi-1-mediated transcriptional repression of the IGF-IR. This mechanism has significant functional and therapeutic implications that were evaluated. IGF-IR expression positively correlates with PTEN and inversely correlates with NRP2 in prostate tumors. NRP2 is a robust biomarker for predicting response to IGF-IR therapy because prostate carcinomas that express NRP2 exhibit low levels of IGF-IR. Conversely, targeting NRP2 is only modestly effective because NRP2 inhibition induces compensatory IGF-IR signaling. Inhibition of both NRP2 and IGF-IR, however, completely blocks tumor growth in vivo. |
| doi_str_mv | 10.1158/2159-8290.cd-12-0085 |
| format | Article |
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VEGF/NRP2 signaling represses insulin-like growth factor-1 receptor (IGF-IR) expression and signaling, and the mechanism involves Bmi-1-mediated transcriptional repression of the IGF-IR. This mechanism has significant functional and therapeutic implications that were evaluated. IGF-IR expression positively correlates with PTEN and inversely correlates with NRP2 in prostate tumors. NRP2 is a robust biomarker for predicting response to IGF-IR therapy because prostate carcinomas that express NRP2 exhibit low levels of IGF-IR. Conversely, targeting NRP2 is only modestly effective because NRP2 inhibition induces compensatory IGF-IR signaling. 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Inhibition of both NRP2 and IGF-IR, however, completely blocks tumor growth in vivo.</description><subject>Animals</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation</subject><subject>Humans</subject><subject>JNK Mitogen-Activated Protein Kinases - genetics</subject><subject>JNK Mitogen-Activated Protein Kinases - metabolism</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Mice, Knockout</subject><subject>Neuropilin-2 - metabolism</subject><subject>Polycomb Repressive Complex 1 - genetics</subject><subject>Polycomb Repressive Complex 1 - metabolism</subject><subject>Prostatic Neoplasms - genetics</subject><subject>Prostatic Neoplasms - metabolism</subject><subject>PTEN Phosphohydrolase - deficiency</subject><subject>PTEN Phosphohydrolase - genetics</subject><subject>Receptor, IGF Type 1 - genetics</subject><subject>Receptor, IGF Type 1 - metabolism</subject><subject>RNA Interference</subject><subject>RNA, Small Interfering</subject><subject>Signal Transduction - genetics</subject><subject>Transcription, Genetic</subject><subject>Transcriptional Activation</subject><subject>Transplantation, Heterologous</subject><subject>Vascular Endothelial Growth Factor A - genetics</subject><subject>Vascular Endothelial Growth Factor A - metabolism</subject><issn>2159-8274</issn><issn>2159-8290</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kE1LAzEQhoMoKtp_IJKjl9R8mt2jVlsLgiDqNaTJpK7sZutmV_DmTzertXOZEJ43k3kQOmN0ypgqLjlTJSl4SafOE8YJpYXaQ8e76_3dWcsjNEnpneaSpVRUH6IjznWuq_IYfb_eLeaXEYau3VR1FQnHHayH2vZVG3Eb8E1TEYZt9Ni1McHHALHPyKaDlLbIcjEnyyfsIVQRsMWx_YQaN-DebKxSMyJ2vf4NfALedG3qbQ_Y2eigO0UHwdYJJtt-gl7md8-ze_LwuFjOrh-IE0IqAsALCE4Hr60PoL2Q1F-BpJzzUnjlmQ9SOeagDAIUt2JVahDKMilWxUqLE3Tx926en5dIvWmq5KCubYR2SIZxoRUttRIZlX-oy19NHQSz6arGdl-GUTPqN6NbM3o2s9ucNKP-HDvfThhWDfhd6F-2-AH0_4GV</recordid><startdate>201210</startdate><enddate>201210</enddate><creator>Goel, Hira Lal</creator><creator>Chang, Cheng</creator><creator>Pursell, Bryan</creator><creator>Leav, Irwin</creator><creator>Lyle, Stephen</creator><creator>Xi, Hualin Simon</creator><creator>Hsieh, Chung-Cheng</creator><creator>Adisetiyo, Helty</creator><creator>Roy-Burman, Pradip</creator><creator>Coleman, Ilsa M</creator><creator>Nelson, Peter S</creator><creator>Vessella, Robert L</creator><creator>Davis, Roger J</creator><creator>Plymate, Stephen R</creator><creator>Mercurio, Arthur M</creator><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></search><sort><creationdate>201210</creationdate><title>VEGF/neuropilin-2 regulation of Bmi-1 and consequent repression of IGF-IR define a novel mechanism of aggressive prostate cancer</title><author>Goel, Hira Lal ; Chang, Cheng ; Pursell, Bryan ; Leav, Irwin ; Lyle, Stephen ; Xi, Hualin Simon ; Hsieh, Chung-Cheng ; Adisetiyo, Helty ; Roy-Burman, Pradip ; Coleman, Ilsa M ; Nelson, Peter S ; Vessella, Robert L ; Davis, Roger J ; Plymate, Stephen R ; Mercurio, Arthur M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3345-ee28efc7fd7adfe7d340d6e4022293d5d1df45c1ce9f3e52a3b97e35a143b8b73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Animals</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation</topic><topic>Humans</topic><topic>JNK Mitogen-Activated Protein Kinases - genetics</topic><topic>JNK Mitogen-Activated Protein Kinases - metabolism</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Mice, Knockout</topic><topic>Neuropilin-2 - metabolism</topic><topic>Polycomb Repressive Complex 1 - genetics</topic><topic>Polycomb Repressive Complex 1 - metabolism</topic><topic>Prostatic Neoplasms - genetics</topic><topic>Prostatic Neoplasms - metabolism</topic><topic>PTEN Phosphohydrolase - deficiency</topic><topic>PTEN Phosphohydrolase - genetics</topic><topic>Receptor, IGF Type 1 - genetics</topic><topic>Receptor, IGF Type 1 - metabolism</topic><topic>RNA Interference</topic><topic>RNA, Small Interfering</topic><topic>Signal Transduction - genetics</topic><topic>Transcription, Genetic</topic><topic>Transcriptional Activation</topic><topic>Transplantation, Heterologous</topic><topic>Vascular Endothelial Growth Factor A - genetics</topic><topic>Vascular Endothelial Growth Factor A - metabolism</topic><toplevel>online_resources</toplevel><creatorcontrib>Goel, Hira Lal</creatorcontrib><creatorcontrib>Chang, Cheng</creatorcontrib><creatorcontrib>Pursell, Bryan</creatorcontrib><creatorcontrib>Leav, Irwin</creatorcontrib><creatorcontrib>Lyle, Stephen</creatorcontrib><creatorcontrib>Xi, Hualin Simon</creatorcontrib><creatorcontrib>Hsieh, Chung-Cheng</creatorcontrib><creatorcontrib>Adisetiyo, Helty</creatorcontrib><creatorcontrib>Roy-Burman, Pradip</creatorcontrib><creatorcontrib>Coleman, Ilsa M</creatorcontrib><creatorcontrib>Nelson, Peter S</creatorcontrib><creatorcontrib>Vessella, Robert L</creatorcontrib><creatorcontrib>Davis, Roger J</creatorcontrib><creatorcontrib>Plymate, Stephen R</creatorcontrib><creatorcontrib>Mercurio, Arthur M</creatorcontrib><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><jtitle>Cancer discovery</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Goel, Hira Lal</au><au>Chang, Cheng</au><au>Pursell, Bryan</au><au>Leav, Irwin</au><au>Lyle, Stephen</au><au>Xi, Hualin Simon</au><au>Hsieh, Chung-Cheng</au><au>Adisetiyo, Helty</au><au>Roy-Burman, Pradip</au><au>Coleman, Ilsa M</au><au>Nelson, Peter S</au><au>Vessella, Robert L</au><au>Davis, Roger J</au><au>Plymate, Stephen R</au><au>Mercurio, Arthur M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>VEGF/neuropilin-2 regulation of Bmi-1 and consequent repression of IGF-IR define a novel mechanism of aggressive prostate cancer</atitle><jtitle>Cancer discovery</jtitle><addtitle>Cancer Discov</addtitle><date>2012-10</date><risdate>2012</risdate><volume>2</volume><issue>10</issue><spage>906</spage><epage>921</epage><pages>906-921</pages><issn>2159-8274</issn><eissn>2159-8290</eissn><abstract>We show that the VEGF receptor neuropilin-2 (NRP2) is associated with high-grade, PTEN-null prostate cancer and that its expression in tumor cells is induced by PTEN loss as a consequence of c-Jun activation. 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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; American Association for Cancer Research |
| subjects | Animals Cell Line, Tumor Cell Proliferation Humans JNK Mitogen-Activated Protein Kinases - genetics JNK Mitogen-Activated Protein Kinases - metabolism Male Mice Mice, Inbred BALB C Mice, Knockout Neuropilin-2 - metabolism Polycomb Repressive Complex 1 - genetics Polycomb Repressive Complex 1 - metabolism Prostatic Neoplasms - genetics Prostatic Neoplasms - metabolism PTEN Phosphohydrolase - deficiency PTEN Phosphohydrolase - genetics Receptor, IGF Type 1 - genetics Receptor, IGF Type 1 - metabolism RNA Interference RNA, Small Interfering Signal Transduction - genetics Transcription, Genetic Transcriptional Activation Transplantation, Heterologous Vascular Endothelial Growth Factor A - genetics Vascular Endothelial Growth Factor A - metabolism |
| title | VEGF/neuropilin-2 regulation of Bmi-1 and consequent repression of IGF-IR define a novel mechanism of aggressive prostate cancer |
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