The essential role of PIM kinases in sarcoma growth and bone invasion
PIM kinases are a family of serine/threonine kinases composed of three different isoforms (PIM1, PIM 2 and PIM 3) that are highly homologous. Their expression is mediated by the JAK/STAT signalling pathway, providing survival and cell cycle transition signals. PIM kinases are heavily targeted for an...
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Veröffentlicht in: | Carcinogenesis (New York) 2012-08, Vol.33 (8), p.1479-1486 |
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creator | NARLIK-GRASSOW, Maja BLANCO-APARICIO, Carmen CECILIA, Yolanda PEREGRINA, Sandra GARCIA-SERELDE, Beatriz MUNOZ-GALVAN, Sandra CANAMERO, Marta CARNERO, Amancio |
description | PIM kinases are a family of serine/threonine kinases composed of three different isoforms (PIM1, PIM 2 and PIM 3) that are highly homologous. Their expression is mediated by the JAK/STAT signalling pathway, providing survival and cell cycle transition signals. PIM kinases are heavily targeted for anticancer drug discovery. However, very little is known about the relative contribution of the different isoforms to the tumourigenesis process in vivo, and how their individual inhibition might affect tumour growth. Taking advantage of genetically modified mice, we explored whether the inhibition of specific isoforms is required to prevent sarcomas induced by 3-methylcholanthrene carcinogenic treatment. We found that absence of Pim2 and Pim3 greatly reduced sarcoma growth to a similar extent to the absence of all three isoforms. This model of sarcoma generally produces bone invasion by the tumour cells. Lack of Pim2 and Pim3 reduced tumour-induced bone invasion by 70%, which is comparable with the reduction of tumour-induced bone invasion in the absence of all three isoforms. Similar results were obtained in mouse embryonic fibroblasts (MEFs) derived from these knockout (KO) mice, where double Pim2/3 KO MEFs already showed reduced proliferation and were resistant to oncogenic transformation by the RAS oncogene. Our data also suggest an important role of Gsk3β phosphorylation in the process of tumourigenesis. |
doi_str_mv | 10.1093/carcin/bgs176 |
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Their expression is mediated by the JAK/STAT signalling pathway, providing survival and cell cycle transition signals. PIM kinases are heavily targeted for anticancer drug discovery. However, very little is known about the relative contribution of the different isoforms to the tumourigenesis process in vivo, and how their individual inhibition might affect tumour growth. Taking advantage of genetically modified mice, we explored whether the inhibition of specific isoforms is required to prevent sarcomas induced by 3-methylcholanthrene carcinogenic treatment. We found that absence of Pim2 and Pim3 greatly reduced sarcoma growth to a similar extent to the absence of all three isoforms. This model of sarcoma generally produces bone invasion by the tumour cells. Lack of Pim2 and Pim3 reduced tumour-induced bone invasion by 70%, which is comparable with the reduction of tumour-induced bone invasion in the absence of all three isoforms. Similar results were obtained in mouse embryonic fibroblasts (MEFs) derived from these knockout (KO) mice, where double Pim2/3 KO MEFs already showed reduced proliferation and were resistant to oncogenic transformation by the RAS oncogene. Our data also suggest an important role of Gsk3β phosphorylation in the process of tumourigenesis.</description><identifier>ISSN: 0143-3334</identifier><identifier>EISSN: 1460-2180</identifier><identifier>DOI: 10.1093/carcin/bgs176</identifier><identifier>PMID: 22623646</identifier><identifier>CODEN: CRNGDP</identifier><language>eng</language><publisher>Oxford: Oxford University Press</publisher><subject>3-Methylcholanthrene ; Animals ; Biological and medical sciences ; Bone and Bones - pathology ; Carcinogenesis, carcinogens and anticarcinogens ; Carcinogens - toxicity ; Cell Line ; Cell Proliferation ; Cells, Cultured ; Medical sciences ; Methylcholanthrene - toxicity ; Mice ; Mice, Knockout ; Neoplasm Invasiveness ; Proto-Oncogene Proteins c-pim-1 - metabolism ; Sarcoma, Experimental - chemically induced ; Sarcoma, Experimental - enzymology ; Sarcoma, Experimental - pathology ; Tumors</subject><ispartof>Carcinogenesis (New York), 2012-08, Vol.33 (8), p.1479-1486</ispartof><rights>2015 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c461t-80f304a61729a18a37c6d56482c2beb5278439edf950d793aace65429d9b2fdd3</citedby><cites>FETCH-LOGICAL-c461t-80f304a61729a18a37c6d56482c2beb5278439edf950d793aace65429d9b2fdd3</cites></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=26254882$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22623646$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>NARLIK-GRASSOW, Maja</creatorcontrib><creatorcontrib>BLANCO-APARICIO, Carmen</creatorcontrib><creatorcontrib>CECILIA, Yolanda</creatorcontrib><creatorcontrib>PEREGRINA, Sandra</creatorcontrib><creatorcontrib>GARCIA-SERELDE, Beatriz</creatorcontrib><creatorcontrib>MUNOZ-GALVAN, Sandra</creatorcontrib><creatorcontrib>CANAMERO, Marta</creatorcontrib><creatorcontrib>CARNERO, Amancio</creatorcontrib><title>The essential role of PIM kinases in sarcoma growth and bone invasion</title><title>Carcinogenesis (New York)</title><addtitle>Carcinogenesis</addtitle><description>PIM kinases are a family of serine/threonine kinases composed of three different isoforms (PIM1, PIM 2 and PIM 3) that are highly homologous. Their expression is mediated by the JAK/STAT signalling pathway, providing survival and cell cycle transition signals. PIM kinases are heavily targeted for anticancer drug discovery. However, very little is known about the relative contribution of the different isoforms to the tumourigenesis process in vivo, and how their individual inhibition might affect tumour growth. Taking advantage of genetically modified mice, we explored whether the inhibition of specific isoforms is required to prevent sarcomas induced by 3-methylcholanthrene carcinogenic treatment. We found that absence of Pim2 and Pim3 greatly reduced sarcoma growth to a similar extent to the absence of all three isoforms. This model of sarcoma generally produces bone invasion by the tumour cells. Lack of Pim2 and Pim3 reduced tumour-induced bone invasion by 70%, which is comparable with the reduction of tumour-induced bone invasion in the absence of all three isoforms. Similar results were obtained in mouse embryonic fibroblasts (MEFs) derived from these knockout (KO) mice, where double Pim2/3 KO MEFs already showed reduced proliferation and were resistant to oncogenic transformation by the RAS oncogene. Our data also suggest an important role of Gsk3β phosphorylation in the process of tumourigenesis.</description><subject>3-Methylcholanthrene</subject><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Bone and Bones - pathology</subject><subject>Carcinogenesis, carcinogens and anticarcinogens</subject><subject>Carcinogens - toxicity</subject><subject>Cell Line</subject><subject>Cell Proliferation</subject><subject>Cells, Cultured</subject><subject>Medical sciences</subject><subject>Methylcholanthrene - toxicity</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Neoplasm Invasiveness</subject><subject>Proto-Oncogene Proteins c-pim-1 - metabolism</subject><subject>Sarcoma, Experimental - chemically induced</subject><subject>Sarcoma, Experimental - enzymology</subject><subject>Sarcoma, Experimental - pathology</subject><subject>Tumors</subject><issn>0143-3334</issn><issn>1460-2180</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqF0D1PwzAUhWELgWgpjKzICxJLqL_iJCOqClQqgqHM0Y3jtIHELr4piH9PUAqMTB786FzpJeScs2vOMjk1EEztpsUaeaIPyJgrzSLBU3ZIxowrGUkp1YicIL4wxrWMs2MyEkILqZUek_lqY6lFtK6roaHBN5b6ij4tHuhr7QAt0tpR7I_4Fug6-I9uQ8GVtPDO9l_vgLV3p-Soggbt2f6dkOfb-Wp2Hy0f7xazm2VklOZdlLJKMgWaJyIDnoJMjC5jrVJhRGGLWCSpkpktqyxmZZJJAGN1rERWZoWoylJOyNWwuw3-bWexy9sajW0acNbvMOeq32JaC_0_ZVLGMlaK9TQaqAkeMdgq34a6hfDZo_w7cj5EzofIvb_YT--K1pa_-qdqDy73ANBAUwVwpsY_p0Ws0lTIL2JthPk</recordid><startdate>20120801</startdate><enddate>20120801</enddate><creator>NARLIK-GRASSOW, Maja</creator><creator>BLANCO-APARICIO, Carmen</creator><creator>CECILIA, Yolanda</creator><creator>PEREGRINA, Sandra</creator><creator>GARCIA-SERELDE, Beatriz</creator><creator>MUNOZ-GALVAN, Sandra</creator><creator>CANAMERO, Marta</creator><creator>CARNERO, Amancio</creator><general>Oxford University Press</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>7TO</scope><scope>H94</scope></search><sort><creationdate>20120801</creationdate><title>The essential role of PIM kinases in sarcoma growth and bone invasion</title><author>NARLIK-GRASSOW, Maja ; BLANCO-APARICIO, Carmen ; CECILIA, Yolanda ; PEREGRINA, Sandra ; GARCIA-SERELDE, Beatriz ; MUNOZ-GALVAN, Sandra ; CANAMERO, Marta ; CARNERO, Amancio</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c461t-80f304a61729a18a37c6d56482c2beb5278439edf950d793aace65429d9b2fdd3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>3-Methylcholanthrene</topic><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Bone and Bones - pathology</topic><topic>Carcinogenesis, carcinogens and anticarcinogens</topic><topic>Carcinogens - toxicity</topic><topic>Cell Line</topic><topic>Cell Proliferation</topic><topic>Cells, Cultured</topic><topic>Medical sciences</topic><topic>Methylcholanthrene - toxicity</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Neoplasm Invasiveness</topic><topic>Proto-Oncogene Proteins c-pim-1 - metabolism</topic><topic>Sarcoma, Experimental - chemically induced</topic><topic>Sarcoma, Experimental - enzymology</topic><topic>Sarcoma, Experimental - pathology</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>NARLIK-GRASSOW, Maja</creatorcontrib><creatorcontrib>BLANCO-APARICIO, Carmen</creatorcontrib><creatorcontrib>CECILIA, Yolanda</creatorcontrib><creatorcontrib>PEREGRINA, Sandra</creatorcontrib><creatorcontrib>GARCIA-SERELDE, Beatriz</creatorcontrib><creatorcontrib>MUNOZ-GALVAN, Sandra</creatorcontrib><creatorcontrib>CANAMERO, Marta</creatorcontrib><creatorcontrib>CARNERO, Amancio</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>Oncogenes and Growth Factors Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><jtitle>Carcinogenesis (New York)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>NARLIK-GRASSOW, Maja</au><au>BLANCO-APARICIO, Carmen</au><au>CECILIA, Yolanda</au><au>PEREGRINA, Sandra</au><au>GARCIA-SERELDE, Beatriz</au><au>MUNOZ-GALVAN, Sandra</au><au>CANAMERO, Marta</au><au>CARNERO, Amancio</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The essential role of PIM kinases in sarcoma growth and bone invasion</atitle><jtitle>Carcinogenesis (New York)</jtitle><addtitle>Carcinogenesis</addtitle><date>2012-08-01</date><risdate>2012</risdate><volume>33</volume><issue>8</issue><spage>1479</spage><epage>1486</epage><pages>1479-1486</pages><issn>0143-3334</issn><eissn>1460-2180</eissn><coden>CRNGDP</coden><abstract>PIM kinases are a family of serine/threonine kinases composed of three different isoforms (PIM1, PIM 2 and PIM 3) that are highly homologous. Their expression is mediated by the JAK/STAT signalling pathway, providing survival and cell cycle transition signals. PIM kinases are heavily targeted for anticancer drug discovery. However, very little is known about the relative contribution of the different isoforms to the tumourigenesis process in vivo, and how their individual inhibition might affect tumour growth. Taking advantage of genetically modified mice, we explored whether the inhibition of specific isoforms is required to prevent sarcomas induced by 3-methylcholanthrene carcinogenic treatment. We found that absence of Pim2 and Pim3 greatly reduced sarcoma growth to a similar extent to the absence of all three isoforms. This model of sarcoma generally produces bone invasion by the tumour cells. Lack of Pim2 and Pim3 reduced tumour-induced bone invasion by 70%, which is comparable with the reduction of tumour-induced bone invasion in the absence of all three isoforms. Similar results were obtained in mouse embryonic fibroblasts (MEFs) derived from these knockout (KO) mice, where double Pim2/3 KO MEFs already showed reduced proliferation and were resistant to oncogenic transformation by the RAS oncogene. Our data also suggest an important role of Gsk3β phosphorylation in the process of tumourigenesis.</abstract><cop>Oxford</cop><pub>Oxford University Press</pub><pmid>22623646</pmid><doi>10.1093/carcin/bgs176</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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subjects | 3-Methylcholanthrene Animals Biological and medical sciences Bone and Bones - pathology Carcinogenesis, carcinogens and anticarcinogens Carcinogens - toxicity Cell Line Cell Proliferation Cells, Cultured Medical sciences Methylcholanthrene - toxicity Mice Mice, Knockout Neoplasm Invasiveness Proto-Oncogene Proteins c-pim-1 - metabolism Sarcoma, Experimental - chemically induced Sarcoma, Experimental - enzymology Sarcoma, Experimental - pathology Tumors |
title | The essential role of PIM kinases in sarcoma growth and bone invasion |
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