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Upregulation of IGF2R evades lysosomal dysfunction-induced apoptosis of cervical cancer cells via transport of cathepsins
Cervical cancer is the most common gynecological malignancy in the world; however, the survival rates of advanced-stage and recurrent cervical cancer patients remain poor. The multifaced protein insulin-like growth factor 2 receptor (IGF2R) has various ligands, represented as IGF-2 and mannose-6-pho...
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Published in: | Cell death & disease 2019-11, Vol.10 (12), p.876-17, Article 876 |
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creator | Takeda, Takashi Komatsu, Masayuki Chiwaki, Fumiko Komatsuzaki, Rie Nakamura, Kanako Tsuji, Kosuke Kobayashi, Yusuke Tominaga, Eiichiro Ono, Masaya Banno, Kouji Aoki, Daisuke Sasaki, Hiroki |
description | Cervical cancer is the most common gynecological malignancy in the world; however, the survival rates of advanced-stage and recurrent cervical cancer patients remain poor. The multifaced protein insulin-like growth factor 2 receptor (IGF2R) has various ligands, represented as IGF-2 and mannose-6-phosphate (M6P)-tagged proteins. Regarding its antagonistic activity as an IGF1R signal,
IGF2R
is currently considered a tumor suppressor gene, whereas its significance as an M6P receptor is still unclear. Here, on the basis of transcriptome analysis of TCGA and GEO open datasets, we show that IGF2R is upregulated and correlated with poor prognosis in cervical cancer. Several experiments using cervical cancer cell lines revealed that IGF2R depletion induced apoptosis, decreased cell viability, and increased vulnerability to certain anticancer drug cisplatin. In contrast to its negligible impact in IGF1R signaling, loss of IGF2R disrupted the Golgi-to-lysosome transport of M6P-tagged cathepsins, resulting in decreased lysosomal activity, with their abnormal accumulation and dysfunction of both autophagy and mitophagy, which cause the accumulation of misfolded proteins and production of reactive oxygen species. Taken together, IGF2R has an oncogenic role through transportation of M6P-tagged cargo in cervical cancer and can be used as a predictive biomarker for prognostic classification. |
doi_str_mv | 10.1038/s41419-019-2117-9 |
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IGF2R
is currently considered a tumor suppressor gene, whereas its significance as an M6P receptor is still unclear. Here, on the basis of transcriptome analysis of TCGA and GEO open datasets, we show that IGF2R is upregulated and correlated with poor prognosis in cervical cancer. Several experiments using cervical cancer cell lines revealed that IGF2R depletion induced apoptosis, decreased cell viability, and increased vulnerability to certain anticancer drug cisplatin. In contrast to its negligible impact in IGF1R signaling, loss of IGF2R disrupted the Golgi-to-lysosome transport of M6P-tagged cathepsins, resulting in decreased lysosomal activity, with their abnormal accumulation and dysfunction of both autophagy and mitophagy, which cause the accumulation of misfolded proteins and production of reactive oxygen species. Taken together, IGF2R has an oncogenic role through transportation of M6P-tagged cargo in cervical cancer and can be used as a predictive biomarker for prognostic classification.</description><identifier>ISSN: 2041-4889</identifier><identifier>EISSN: 2041-4889</identifier><identifier>DOI: 10.1038/s41419-019-2117-9</identifier><identifier>PMID: 31748500</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/109 ; 13/2 ; 13/31 ; 13/44 ; 13/89 ; 14 ; 14/63 ; 38/39 ; 631/67/1059/602 ; 631/67/1517/1371 ; 631/80/82/23 ; 82/1 ; 96/95 ; Antibodies ; Apoptosis ; Apoptosis - physiology ; Autophagy ; Biochemistry ; Biomarkers, Tumor - genetics ; Biomarkers, Tumor - metabolism ; Biomedical and Life Sciences ; Cathepsins ; Cathepsins - metabolism ; Cell Biology ; Cell Culture ; Cell viability ; Cervical cancer ; Cervix ; Cisplatin ; Female ; Gene expression ; Gene Knockdown Techniques ; Golgi apparatus ; Golgi Apparatus - genetics ; Golgi Apparatus - metabolism ; Golgi Apparatus - pathology ; Humans ; Immunology ; Insulin ; Insulin-like growth factor II receptors ; Life Sciences ; Lysosomes - genetics ; Lysosomes - metabolism ; Lysosomes - pathology ; Malignancy ; Mannose ; Medical prognosis ; Middle Aged ; Phagocytosis ; Protein folding ; Reactive oxygen species ; Reactive Oxygen Species - metabolism ; Receptor, IGF Type 1 - metabolism ; Receptor, IGF Type 2 - metabolism ; RNA, Messenger - genetics ; RNA, Messenger - metabolism ; Tumor cell lines ; Tumor suppressor genes ; Up-Regulation ; Uterine Cervical Neoplasms - genetics ; Uterine Cervical Neoplasms - metabolism ; Uterine Cervical Neoplasms - pathology</subject><ispartof>Cell death & disease, 2019-11, Vol.10 (12), p.876-17, Article 876</ispartof><rights>The Author(s) 2019</rights><rights>2019. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c536t-6297a2f589373d38f88dcca64ebfea56d96fb0c16bb3506a0c1d13d8ba01cfa63</citedby><cites>FETCH-LOGICAL-c536t-6297a2f589373d38f88dcca64ebfea56d96fb0c16bb3506a0c1d13d8ba01cfa63</cites><orcidid>0000-0001-6686-5742</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.proquest.com/docview/2316416489/fulltextPDF?pq-origsite=primo$$EPDF$$P50$$Gproquest$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/2316416489?pq-origsite=primo$$EHTML$$P50$$Gproquest$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,25753,27924,27925,37012,37013,44590,53791,53793,75126</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31748500$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Takeda, Takashi</creatorcontrib><creatorcontrib>Komatsu, Masayuki</creatorcontrib><creatorcontrib>Chiwaki, Fumiko</creatorcontrib><creatorcontrib>Komatsuzaki, Rie</creatorcontrib><creatorcontrib>Nakamura, Kanako</creatorcontrib><creatorcontrib>Tsuji, Kosuke</creatorcontrib><creatorcontrib>Kobayashi, Yusuke</creatorcontrib><creatorcontrib>Tominaga, Eiichiro</creatorcontrib><creatorcontrib>Ono, Masaya</creatorcontrib><creatorcontrib>Banno, Kouji</creatorcontrib><creatorcontrib>Aoki, Daisuke</creatorcontrib><creatorcontrib>Sasaki, Hiroki</creatorcontrib><title>Upregulation of IGF2R evades lysosomal dysfunction-induced apoptosis of cervical cancer cells via transport of cathepsins</title><title>Cell death & disease</title><addtitle>Cell Death Dis</addtitle><addtitle>Cell Death Dis</addtitle><description>Cervical cancer is the most common gynecological malignancy in the world; however, the survival rates of advanced-stage and recurrent cervical cancer patients remain poor. The multifaced protein insulin-like growth factor 2 receptor (IGF2R) has various ligands, represented as IGF-2 and mannose-6-phosphate (M6P)-tagged proteins. Regarding its antagonistic activity as an IGF1R signal,
IGF2R
is currently considered a tumor suppressor gene, whereas its significance as an M6P receptor is still unclear. Here, on the basis of transcriptome analysis of TCGA and GEO open datasets, we show that IGF2R is upregulated and correlated with poor prognosis in cervical cancer. Several experiments using cervical cancer cell lines revealed that IGF2R depletion induced apoptosis, decreased cell viability, and increased vulnerability to certain anticancer drug cisplatin. In contrast to its negligible impact in IGF1R signaling, loss of IGF2R disrupted the Golgi-to-lysosome transport of M6P-tagged cathepsins, resulting in decreased lysosomal activity, with their abnormal accumulation and dysfunction of both autophagy and mitophagy, which cause the accumulation of misfolded proteins and production of reactive oxygen species. Taken together, IGF2R has an oncogenic role through transportation of M6P-tagged cargo in cervical cancer and can be used as a predictive biomarker for prognostic classification.</description><subject>13/109</subject><subject>13/2</subject><subject>13/31</subject><subject>13/44</subject><subject>13/89</subject><subject>14</subject><subject>14/63</subject><subject>38/39</subject><subject>631/67/1059/602</subject><subject>631/67/1517/1371</subject><subject>631/80/82/23</subject><subject>82/1</subject><subject>96/95</subject><subject>Antibodies</subject><subject>Apoptosis</subject><subject>Apoptosis - physiology</subject><subject>Autophagy</subject><subject>Biochemistry</subject><subject>Biomarkers, Tumor - genetics</subject><subject>Biomarkers, Tumor - metabolism</subject><subject>Biomedical and Life Sciences</subject><subject>Cathepsins</subject><subject>Cathepsins - metabolism</subject><subject>Cell Biology</subject><subject>Cell Culture</subject><subject>Cell viability</subject><subject>Cervical cancer</subject><subject>Cervix</subject><subject>Cisplatin</subject><subject>Female</subject><subject>Gene expression</subject><subject>Gene Knockdown Techniques</subject><subject>Golgi apparatus</subject><subject>Golgi Apparatus - genetics</subject><subject>Golgi Apparatus - metabolism</subject><subject>Golgi Apparatus - pathology</subject><subject>Humans</subject><subject>Immunology</subject><subject>Insulin</subject><subject>Insulin-like growth factor II receptors</subject><subject>Life Sciences</subject><subject>Lysosomes - genetics</subject><subject>Lysosomes - metabolism</subject><subject>Lysosomes - pathology</subject><subject>Malignancy</subject><subject>Mannose</subject><subject>Medical prognosis</subject><subject>Middle Aged</subject><subject>Phagocytosis</subject><subject>Protein folding</subject><subject>Reactive oxygen species</subject><subject>Reactive Oxygen Species - metabolism</subject><subject>Receptor, IGF Type 1 - metabolism</subject><subject>Receptor, IGF Type 2 - metabolism</subject><subject>RNA, Messenger - genetics</subject><subject>RNA, Messenger - metabolism</subject><subject>Tumor cell lines</subject><subject>Tumor suppressor genes</subject><subject>Up-Regulation</subject><subject>Uterine Cervical Neoplasms - 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metabolism</topic><topic>Receptor, IGF Type 1 - metabolism</topic><topic>Receptor, IGF Type 2 - metabolism</topic><topic>RNA, Messenger - genetics</topic><topic>RNA, Messenger - metabolism</topic><topic>Tumor cell lines</topic><topic>Tumor suppressor genes</topic><topic>Up-Regulation</topic><topic>Uterine Cervical Neoplasms - genetics</topic><topic>Uterine Cervical Neoplasms - metabolism</topic><topic>Uterine Cervical Neoplasms - pathology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Takeda, Takashi</creatorcontrib><creatorcontrib>Komatsu, Masayuki</creatorcontrib><creatorcontrib>Chiwaki, Fumiko</creatorcontrib><creatorcontrib>Komatsuzaki, Rie</creatorcontrib><creatorcontrib>Nakamura, Kanako</creatorcontrib><creatorcontrib>Tsuji, Kosuke</creatorcontrib><creatorcontrib>Kobayashi, Yusuke</creatorcontrib><creatorcontrib>Tominaga, Eiichiro</creatorcontrib><creatorcontrib>Ono, Masaya</creatorcontrib><creatorcontrib>Banno, Kouji</creatorcontrib><creatorcontrib>Aoki, Daisuke</creatorcontrib><creatorcontrib>Sasaki, Hiroki</creatorcontrib><collection>Springer Nature OA Free Journals</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>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</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>ProQuest Central (Alumni)</collection><collection>ProQuest Central</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>AUTh Library subscriptions: ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</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>ProQuest Science Journals</collection><collection>Biological Science Database</collection><collection>Publicly Available Content Database</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 China</collection><collection>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cell death & disease</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Takeda, Takashi</au><au>Komatsu, Masayuki</au><au>Chiwaki, Fumiko</au><au>Komatsuzaki, Rie</au><au>Nakamura, Kanako</au><au>Tsuji, Kosuke</au><au>Kobayashi, Yusuke</au><au>Tominaga, Eiichiro</au><au>Ono, Masaya</au><au>Banno, Kouji</au><au>Aoki, Daisuke</au><au>Sasaki, Hiroki</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Upregulation of IGF2R evades lysosomal dysfunction-induced apoptosis of cervical cancer cells via transport of cathepsins</atitle><jtitle>Cell death & disease</jtitle><stitle>Cell Death Dis</stitle><addtitle>Cell Death Dis</addtitle><date>2019-11-20</date><risdate>2019</risdate><volume>10</volume><issue>12</issue><spage>876</spage><epage>17</epage><pages>876-17</pages><artnum>876</artnum><issn>2041-4889</issn><eissn>2041-4889</eissn><abstract>Cervical cancer is the most common gynecological malignancy in the world; however, the survival rates of advanced-stage and recurrent cervical cancer patients remain poor. The multifaced protein insulin-like growth factor 2 receptor (IGF2R) has various ligands, represented as IGF-2 and mannose-6-phosphate (M6P)-tagged proteins. Regarding its antagonistic activity as an IGF1R signal,
IGF2R
is currently considered a tumor suppressor gene, whereas its significance as an M6P receptor is still unclear. Here, on the basis of transcriptome analysis of TCGA and GEO open datasets, we show that IGF2R is upregulated and correlated with poor prognosis in cervical cancer. Several experiments using cervical cancer cell lines revealed that IGF2R depletion induced apoptosis, decreased cell viability, and increased vulnerability to certain anticancer drug cisplatin. In contrast to its negligible impact in IGF1R signaling, loss of IGF2R disrupted the Golgi-to-lysosome transport of M6P-tagged cathepsins, resulting in decreased lysosomal activity, with their abnormal accumulation and dysfunction of both autophagy and mitophagy, which cause the accumulation of misfolded proteins and production of reactive oxygen species. Taken together, IGF2R has an oncogenic role through transportation of M6P-tagged cargo in cervical cancer and can be used as a predictive biomarker for prognostic classification.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>31748500</pmid><doi>10.1038/s41419-019-2117-9</doi><tpages>17</tpages><orcidid>https://orcid.org/0000-0001-6686-5742</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | 13/109 13/2 13/31 13/44 13/89 14 14/63 38/39 631/67/1059/602 631/67/1517/1371 631/80/82/23 82/1 96/95 Antibodies Apoptosis Apoptosis - physiology Autophagy Biochemistry Biomarkers, Tumor - genetics Biomarkers, Tumor - metabolism Biomedical and Life Sciences Cathepsins Cathepsins - metabolism Cell Biology Cell Culture Cell viability Cervical cancer Cervix Cisplatin Female Gene expression Gene Knockdown Techniques Golgi apparatus Golgi Apparatus - genetics Golgi Apparatus - metabolism Golgi Apparatus - pathology Humans Immunology Insulin Insulin-like growth factor II receptors Life Sciences Lysosomes - genetics Lysosomes - metabolism Lysosomes - pathology Malignancy Mannose Medical prognosis Middle Aged Phagocytosis Protein folding Reactive oxygen species Reactive Oxygen Species - metabolism Receptor, IGF Type 1 - metabolism Receptor, IGF Type 2 - metabolism RNA, Messenger - genetics RNA, Messenger - metabolism Tumor cell lines Tumor suppressor genes Up-Regulation Uterine Cervical Neoplasms - genetics Uterine Cervical Neoplasms - metabolism Uterine Cervical Neoplasms - pathology |
title | Upregulation of IGF2R evades lysosomal dysfunction-induced apoptosis of cervical cancer cells via transport of cathepsins |
url | http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-25T20%3A20%3A32IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Upregulation%20of%20IGF2R%20evades%20lysosomal%20dysfunction-induced%20apoptosis%20of%20cervical%20cancer%20cells%20via%20transport%20of%20cathepsins&rft.jtitle=Cell%20death%20&%20disease&rft.au=Takeda,%20Takashi&rft.date=2019-11-20&rft.volume=10&rft.issue=12&rft.spage=876&rft.epage=17&rft.pages=876-17&rft.artnum=876&rft.issn=2041-4889&rft.eissn=2041-4889&rft_id=info:doi/10.1038/s41419-019-2117-9&rft_dat=%3Cproquest_pubme%3E2316416489%3C/proquest_pubme%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c536t-6297a2f589373d38f88dcca64ebfea56d96fb0c16bb3506a0c1d13d8ba01cfa63%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=2316416489&rft_id=info:pmid/31748500&rfr_iscdi=true |