Nuclear IGF1R interact with PCNA to preserve DNA replication after DNA-damage in a variety of human cancers
Nuclear IGF1R has been linked to poor outcome in cancer. We recently showed that nuclear IGF1R phosphorylates PCNA and increases DNA damage tolerance. In this paper we aimed to describe this mechanism in cancer tissue as well as in cancer cell lines. In situ proximity ligation assay identified frequ...
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| Veröffentlicht in: | PloS one 2020, Vol.15 (7), p.e0236291-e0236291 |
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| creator | Yang, Chen Zhang, Yifan Chen, Yi Ragaller, Franziska Liu, Mingzhi Corvigno, Sara Dahlstrand, Hanna Carlson, Joseph Chen, Zihua Näsman, Anders Waraky, Ahmed Lin, Yingbo Larsson, Olle Haglund, Felix |
| description | Nuclear IGF1R has been linked to poor outcome in cancer. We recently showed that nuclear IGF1R phosphorylates PCNA and increases DNA damage tolerance. In this paper we aimed to describe this mechanism in cancer tissue as well as in cancer cell lines. In situ proximity ligation assay identified frequent IGF1R and PCNA colocalization in many cancer types. IGF1R/PCNA colocalization was more frequently increased in tumor cells than in adjacent normal, and more prominent in areas with dysplasia and invasion. However, the interaction was often lost in tumors with poor response to neoadjuvant treatment and most metastatic lesions. In two independent cohorts of serous ovarian carcinomas and oropharyngeal squamous cell carcinomas, stronger IGF1R/PCNA colocalization was significantly associated with a higher overall survival. Ex vivo irradiation of ovarian cancer tissue acutely induced IGF1R/PCNA colocalization together with γH2AX-foci formations. In vitro, RAD18 mediated mono-ubiquitination of PCNA during replication stress was dependent on IGF1R kinase activity. DNA fiber analysis revealed that IGF1R activation could rescue stalled DNA replication forks, but only in cancer cells with baseline IGF1R/PCNA interaction. We believe that the IGF1R/PCNA interaction is a basic cellular mechanism to increase DNA stress tolerance during proliferation, but that this mechanism is lost with tumor progression in conjunction with accumulated DNA damage and aberrant strategies to tolerate genomic instability. To exploit this mechanism in IGF1R targeted therapy, IGF1R inhibitors should be explored in the context of concomitant induction of DNA replication stress as well as in earlier clinical stages than previously tried. |
| doi_str_mv | 10.1371/journal.pone.0236291 |
| format | Article |
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We recently showed that nuclear IGF1R phosphorylates PCNA and increases DNA damage tolerance. In this paper we aimed to describe this mechanism in cancer tissue as well as in cancer cell lines. In situ proximity ligation assay identified frequent IGF1R and PCNA colocalization in many cancer types. IGF1R/PCNA colocalization was more frequently increased in tumor cells than in adjacent normal, and more prominent in areas with dysplasia and invasion. However, the interaction was often lost in tumors with poor response to neoadjuvant treatment and most metastatic lesions. In two independent cohorts of serous ovarian carcinomas and oropharyngeal squamous cell carcinomas, stronger IGF1R/PCNA colocalization was significantly associated with a higher overall survival. Ex vivo irradiation of ovarian cancer tissue acutely induced IGF1R/PCNA colocalization together with γH2AX-foci formations. In vitro, RAD18 mediated mono-ubiquitination of PCNA during replication stress was dependent on IGF1R kinase activity. DNA fiber analysis revealed that IGF1R activation could rescue stalled DNA replication forks, but only in cancer cells with baseline IGF1R/PCNA interaction. We believe that the IGF1R/PCNA interaction is a basic cellular mechanism to increase DNA stress tolerance during proliferation, but that this mechanism is lost with tumor progression in conjunction with accumulated DNA damage and aberrant strategies to tolerate genomic instability. To exploit this mechanism in IGF1R targeted therapy, IGF1R inhibitors should be explored in the context of concomitant induction of DNA replication stress as well as in earlier clinical stages than previously tried.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0236291</identifier><identifier>PMID: 32701997</identifier><language>eng</language><publisher>San Francisco: Public Library of Science</publisher><subject>Biology and life sciences ; Breast cancer ; Cancer ; Cancer and Oncology ; Cancer och onkologi ; Cancer therapies ; Cell division ; Cloning ; Colorectal cancer ; Damage accumulation ; Damage tolerance ; Deoxyribonucleic acid ; DNA ; DNA biosynthesis ; DNA damage ; DNA repair ; Dysplasia ; Genomes ; Genomic instability ; Irradiation ; Kinases ; Laboratories ; Medical diagnosis ; Medicin och hälsovetenskap ; Medicine and Health Sciences ; Metastases ; Methods ; Oncology ; Oropharyngolaryngeal carcinoma ; Ovarian cancer ; Ovarian carcinoma ; Pathology ; Proliferating cell nuclear antigen ; Proteins ; Radiation ; Replication ; Replication forks ; Research and analysis methods ; Software ; Squamous cell carcinoma ; Stem cells ; Stress ; Surgery ; Tumor cell lines ; Tumor cells ; Tumors ; Ubiquitination</subject><ispartof>PloS one, 2020, Vol.15 (7), p.e0236291-e0236291</ispartof><rights>2020 Yang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2020 Yang et al 2020 Yang et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c666t-4ef321f5b352b2f30f4553d150ce0a3e83e75e42c42fcacd52e3bf7640314bb53</citedby><cites>FETCH-LOGICAL-c666t-4ef321f5b352b2f30f4553d150ce0a3e83e75e42c42fcacd52e3bf7640314bb53</cites><orcidid>0000-0003-4635-021X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7377393/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7377393/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,552,727,780,784,864,885,2102,2928,4024,23866,27923,27924,27925,53791,53793,79600,79601</link.rule.ids><backlink>$$Uhttps://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-423451$$DView record from Swedish Publication Index$$Hfree_for_read</backlink><backlink>$$Uhttps://gup.ub.gu.se/publication/297538$$DView record from Swedish Publication Index$$Hfree_for_read</backlink><backlink>$$Uhttp://kipublications.ki.se/Default.aspx?queryparsed=id:144857594$$DView record from Swedish Publication Index$$Hfree_for_read</backlink></links><search><contributor>Palle, Komaraiah</contributor><creatorcontrib>Yang, Chen</creatorcontrib><creatorcontrib>Zhang, Yifan</creatorcontrib><creatorcontrib>Chen, Yi</creatorcontrib><creatorcontrib>Ragaller, Franziska</creatorcontrib><creatorcontrib>Liu, Mingzhi</creatorcontrib><creatorcontrib>Corvigno, Sara</creatorcontrib><creatorcontrib>Dahlstrand, Hanna</creatorcontrib><creatorcontrib>Carlson, Joseph</creatorcontrib><creatorcontrib>Chen, Zihua</creatorcontrib><creatorcontrib>Näsman, Anders</creatorcontrib><creatorcontrib>Waraky, Ahmed</creatorcontrib><creatorcontrib>Lin, Yingbo</creatorcontrib><creatorcontrib>Larsson, Olle</creatorcontrib><creatorcontrib>Haglund, Felix</creatorcontrib><title>Nuclear IGF1R interact with PCNA to preserve DNA replication after DNA-damage in a variety of human cancers</title><title>PloS one</title><description>Nuclear IGF1R has been linked to poor outcome in cancer. We recently showed that nuclear IGF1R phosphorylates PCNA and increases DNA damage tolerance. In this paper we aimed to describe this mechanism in cancer tissue as well as in cancer cell lines. In situ proximity ligation assay identified frequent IGF1R and PCNA colocalization in many cancer types. IGF1R/PCNA colocalization was more frequently increased in tumor cells than in adjacent normal, and more prominent in areas with dysplasia and invasion. However, the interaction was often lost in tumors with poor response to neoadjuvant treatment and most metastatic lesions. In two independent cohorts of serous ovarian carcinomas and oropharyngeal squamous cell carcinomas, stronger IGF1R/PCNA colocalization was significantly associated with a higher overall survival. Ex vivo irradiation of ovarian cancer tissue acutely induced IGF1R/PCNA colocalization together with γH2AX-foci formations. In vitro, RAD18 mediated mono-ubiquitination of PCNA during replication stress was dependent on IGF1R kinase activity. DNA fiber analysis revealed that IGF1R activation could rescue stalled DNA replication forks, but only in cancer cells with baseline IGF1R/PCNA interaction. We believe that the IGF1R/PCNA interaction is a basic cellular mechanism to increase DNA stress tolerance during proliferation, but that this mechanism is lost with tumor progression in conjunction with accumulated DNA damage and aberrant strategies to tolerate genomic instability. To exploit this mechanism in IGF1R targeted therapy, IGF1R inhibitors should be explored in the context of concomitant induction of DNA replication stress as well as in earlier clinical stages than previously tried.</description><subject>Biology and life sciences</subject><subject>Breast cancer</subject><subject>Cancer</subject><subject>Cancer and Oncology</subject><subject>Cancer och onkologi</subject><subject>Cancer therapies</subject><subject>Cell division</subject><subject>Cloning</subject><subject>Colorectal cancer</subject><subject>Damage accumulation</subject><subject>Damage tolerance</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA biosynthesis</subject><subject>DNA damage</subject><subject>DNA repair</subject><subject>Dysplasia</subject><subject>Genomes</subject><subject>Genomic instability</subject><subject>Irradiation</subject><subject>Kinases</subject><subject>Laboratories</subject><subject>Medical diagnosis</subject><subject>Medicin och hälsovetenskap</subject><subject>Medicine and Health Sciences</subject><subject>Metastases</subject><subject>Methods</subject><subject>Oncology</subject><subject>Oropharyngolaryngeal carcinoma</subject><subject>Ovarian cancer</subject><subject>Ovarian carcinoma</subject><subject>Pathology</subject><subject>Proliferating cell nuclear antigen</subject><subject>Proteins</subject><subject>Radiation</subject><subject>Replication</subject><subject>Replication forks</subject><subject>Research and analysis methods</subject><subject>Software</subject><subject>Squamous cell carcinoma</subject><subject>Stem cells</subject><subject>Stress</subject><subject>Surgery</subject><subject>Tumor cell lines</subject><subject>Tumor cells</subject><subject>Tumors</subject><subject>Ubiquitination</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>D8T</sourceid><sourceid>DOA</sourceid><recordid>eNp9k19v0zAUxSMEYqPwDZCwxAsPpPi_4xekqmOj0jQQAl4tx7lu06VxcJJO-_a4awcUMZ7iHP_OsX2vbpa9JHhKmCLv1mGMrW2mXWhhiimTVJNH2SnRjOaSYvb4j_VJ9qzv1xgLVkj5NDthVGGitTrNrq9G14CNaHFxTr6guh0gWjegm3pYoc_zqxkaAuoi9BC3gM7Sf4SuqZ0d6tAi6xO-U_PKbuwSkh9ZtLWxhuEWBY9W48a2yNnWQeyfZ0-8bXp4cfhOsm_nH77OP-aXny4W89ll7qSUQ87BM0q8KJmgJfUMey4Eq4jADrBlUDBQAjh1nHpnXSUosNIryTEjvCwFm2Sv9rldE3pzqFNvKKdSpOTETbLFnqiCXZsu1hsbb02wtbkTQlwaG4c6VcZwVqjSOwIFANfY6SIpjHmnOa2khZSV77P6G-jG8ijtIF2nVUqSWhCZeP0g38VQ_TbdGwnnhVBC8_-etRw7k6TluLNQrVKvE__2Qf6s_j67e-k4Gk4ZFyTh7w-FG8sNVA7aIdrm-IZHO229MsuwNYopxTRLAW8OATH8GKEfzKbuHTSNbSGMdy1QDOuC7lrw-i_0343ie8rF0PcR_K_LEGx2Y3DvMrsxMIcxYD8B5mH9Dw</recordid><startdate>2020</startdate><enddate>2020</enddate><creator>Yang, 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IGF1R interact with PCNA to preserve DNA replication after DNA-damage in a variety of human cancers</title><author>Yang, Chen ; Zhang, Yifan ; Chen, Yi ; Ragaller, Franziska ; Liu, Mingzhi ; Corvigno, Sara ; Dahlstrand, Hanna ; Carlson, Joseph ; Chen, Zihua ; Näsman, Anders ; Waraky, Ahmed ; Lin, Yingbo ; Larsson, Olle ; Haglund, Felix</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c666t-4ef321f5b352b2f30f4553d150ce0a3e83e75e42c42fcacd52e3bf7640314bb53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Biology and life sciences</topic><topic>Breast cancer</topic><topic>Cancer</topic><topic>Cancer and Oncology</topic><topic>Cancer och onkologi</topic><topic>Cancer therapies</topic><topic>Cell division</topic><topic>Cloning</topic><topic>Colorectal cancer</topic><topic>Damage accumulation</topic><topic>Damage tolerance</topic><topic>Deoxyribonucleic 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IGF1R interact with PCNA to preserve DNA replication after DNA-damage in a variety of human cancers</atitle><jtitle>PloS one</jtitle><date>2020</date><risdate>2020</risdate><volume>15</volume><issue>7</issue><spage>e0236291</spage><epage>e0236291</epage><pages>e0236291-e0236291</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Nuclear IGF1R has been linked to poor outcome in cancer. We recently showed that nuclear IGF1R phosphorylates PCNA and increases DNA damage tolerance. In this paper we aimed to describe this mechanism in cancer tissue as well as in cancer cell lines. In situ proximity ligation assay identified frequent IGF1R and PCNA colocalization in many cancer types. IGF1R/PCNA colocalization was more frequently increased in tumor cells than in adjacent normal, and more prominent in areas with dysplasia and invasion. However, the interaction was often lost in tumors with poor response to neoadjuvant treatment and most metastatic lesions. In two independent cohorts of serous ovarian carcinomas and oropharyngeal squamous cell carcinomas, stronger IGF1R/PCNA colocalization was significantly associated with a higher overall survival. Ex vivo irradiation of ovarian cancer tissue acutely induced IGF1R/PCNA colocalization together with γH2AX-foci formations. In vitro, RAD18 mediated mono-ubiquitination of PCNA during replication stress was dependent on IGF1R kinase activity. DNA fiber analysis revealed that IGF1R activation could rescue stalled DNA replication forks, but only in cancer cells with baseline IGF1R/PCNA interaction. We believe that the IGF1R/PCNA interaction is a basic cellular mechanism to increase DNA stress tolerance during proliferation, but that this mechanism is lost with tumor progression in conjunction with accumulated DNA damage and aberrant strategies to tolerate genomic instability. To exploit this mechanism in IGF1R targeted therapy, IGF1R inhibitors should be explored in the context of concomitant induction of DNA replication stress as well as in earlier clinical stages than previously tried.</abstract><cop>San Francisco</cop><pub>Public Library of Science</pub><pmid>32701997</pmid><doi>10.1371/journal.pone.0236291</doi><orcidid>https://orcid.org/0000-0003-4635-021X</orcidid><oa>free_for_read</oa></addata></record> |
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| language | eng |
| recordid | cdi_plos_journals_2426532140 |
| source | DOAJ Directory of Open Access Journals; SWEPUB Freely available online; Public Library of Science (PLoS) Journals Open Access; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Biology and life sciences Breast cancer Cancer Cancer and Oncology Cancer och onkologi Cancer therapies Cell division Cloning Colorectal cancer Damage accumulation Damage tolerance Deoxyribonucleic acid DNA DNA biosynthesis DNA damage DNA repair Dysplasia Genomes Genomic instability Irradiation Kinases Laboratories Medical diagnosis Medicin och hälsovetenskap Medicine and Health Sciences Metastases Methods Oncology Oropharyngolaryngeal carcinoma Ovarian cancer Ovarian carcinoma Pathology Proliferating cell nuclear antigen Proteins Radiation Replication Replication forks Research and analysis methods Software Squamous cell carcinoma Stem cells Stress Surgery Tumor cell lines Tumor cells Tumors Ubiquitination |
| title | Nuclear IGF1R interact with PCNA to preserve DNA replication after DNA-damage in a variety of human cancers |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-26T12%3A08%3A27IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Nuclear%20IGF1R%20interact%20with%20PCNA%20to%20preserve%20DNA%20replication%20after%20DNA-damage%20in%20a%20variety%20of%20human%20cancers&rft.jtitle=PloS%20one&rft.au=Yang,%20Chen&rft.date=2020&rft.volume=15&rft.issue=7&rft.spage=e0236291&rft.epage=e0236291&rft.pages=e0236291-e0236291&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0236291&rft_dat=%3Cproquest_plos_%3E2426532140%3C/proquest_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2426532140&rft_id=info:pmid/32701997&rft_doaj_id=oai_doaj_org_article_4387bfc1e8ee490c9843833fc942d6ae&rfr_iscdi=true |