Induction of cellular senescence by doxorubicin is associated with upregulated miR-375 and induction of autophagy in K562 cells
Cellular senescence is a specialized form of growth arrest that is generally irreversible. Upregulated p16, p53, and p21 expression and silencing of E2F target genes have been characterized to promote the establishment of senescence. It can be further aided by the transcriptional repression of proli...
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| description | Cellular senescence is a specialized form of growth arrest that is generally irreversible. Upregulated p16, p53, and p21 expression and silencing of E2F target genes have been characterized to promote the establishment of senescence. It can be further aided by the transcriptional repression of proliferation-associated genes by the action of HP1γ, HMGA, and DNMT proteins to produce a repressive chromatin environment. Therefore, senescence has been suggested to functions as a natural brake for tumor development and plays a critical role in tumor suppression and aging.
An in vitro senescence model has been established by using K562 cells treated with 50 nM doxorubicin (DOX). Since p53 and p16 are homozygously deleted in the K562 cells, the DOX-induced senescence in K562 cells ought to be independent of p53 and p16-pRb pathways. Indeed, no change in the expression of the typical senescence-associated premalignant cell markers in the DOX-induced senescent K562 cells was found. MicroRNA profiling revealed upregulated miR-375 in DOX-induced senescent K562 cells. Treatment with miR-375 inhibitor was able to reverse the proliferation ability suppressed by DOX (p |
| doi_str_mv | 10.1371/journal.pone.0037205 |
| format | Article |
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An in vitro senescence model has been established by using K562 cells treated with 50 nM doxorubicin (DOX). Since p53 and p16 are homozygously deleted in the K562 cells, the DOX-induced senescence in K562 cells ought to be independent of p53 and p16-pRb pathways. Indeed, no change in the expression of the typical senescence-associated premalignant cell markers in the DOX-induced senescent K562 cells was found. MicroRNA profiling revealed upregulated miR-375 in DOX-induced senescent K562 cells. Treatment with miR-375 inhibitor was able to reverse the proliferation ability suppressed by DOX (p<0.05) and overexpression of miR-375 suppressed the normal proliferation of K562 cells. Upregulated miR-375 expression was associated with downregulated expression of 14-3-3zeta and SP1 genes. Autophagy was also investigated since DOX treatment was able to induce cells entering senescence and eventually lead to cell death. Among the 24 human autophagy-related genes examined, a 12-fold increase of ATG9B at day 4 and a 20-fold increase of ATG18 at day 2 after DOX treatment were noted.
This study has demonstrated that in the absence of p53 and p16, the induction of senescence by DOX was associated with upregulation of miR-375 and autophagy initiation. The anti-proliferative function of miR-375 is possibly exerted, at least in part, by targeting 14-3-3zeta and SP1 genes.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0037205</identifier><identifier>PMID: 22606351</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>14-3-3 Proteins - genetics ; Aging ; Aging (natural) ; Analysis ; Anthracyclines ; Apoptosis ; Autophagy ; Autophagy - drug effects ; Biology ; Cell cycle ; Cell death ; Cell growth ; Cell proliferation ; Cellular Senescence - drug effects ; Cellular Senescence - genetics ; Cellular Senescence - physiology ; Cervical cancer ; Chromatin ; Chromosomal proteins ; Dehydrogenases ; Development and progression ; Doxorubicin ; Doxorubicin - pharmacology ; E2F protein ; Esophageal cancer ; Gastric cancer ; Gene expression ; Gene silencing ; Genes ; Genes, p16 ; Genes, p53 ; Genetic aspects ; Hematology ; Hospitals ; Humans ; Insulin-like growth factors ; Internal medicine ; K562 Cells ; Kinases ; Liver cancer ; Medicine ; Metastasis ; MicroRNA ; MicroRNAs ; MicroRNAs - genetics ; miRNA ; Models, Biological ; Morphology ; Oncology ; p53 Protein ; Phagocytosis ; Proteins ; Ribonucleic acid ; RNA ; Senescence ; Sp1 protein ; Sp1 Transcription Factor - genetics ; Stomach cancer ; Transcription (Genetics) ; Transcription factors ; Tumor proteins ; Tumor suppression ; Up-Regulation - drug effects</subject><ispartof>PloS one, 2012-05, Vol.7 (5), p.e37205</ispartof><rights>COPYRIGHT 2012 Public Library of Science</rights><rights>2012 Yang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://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>Yang et al. 2012</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-15d09b16153ac3bdf193a793b439b957257c1a47685d8d4de378f4ea40e95a483</citedby><cites>FETCH-LOGICAL-c692t-15d09b16153ac3bdf193a793b439b957257c1a47685d8d4de378f4ea40e95a483</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3350486/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3350486/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2095,2914,23846,27903,27904,53769,53771,79346,79347</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22606351$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Chuang, Eric Y.</contributor><creatorcontrib>Yang, Ming-Yu</creatorcontrib><creatorcontrib>Lin, Pai-Mei</creatorcontrib><creatorcontrib>Liu, Yi-Chang</creatorcontrib><creatorcontrib>Hsiao, Hui-Hua</creatorcontrib><creatorcontrib>Yang, Wen-Chi</creatorcontrib><creatorcontrib>Hsu, Jui-Feng</creatorcontrib><creatorcontrib>Hsu, Cheng-Ming</creatorcontrib><creatorcontrib>Lin, Sheng-Fung</creatorcontrib><title>Induction of cellular senescence by doxorubicin is associated with upregulated miR-375 and induction of autophagy in K562 cells</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Cellular senescence is a specialized form of growth arrest that is generally irreversible. Upregulated p16, p53, and p21 expression and silencing of E2F target genes have been characterized to promote the establishment of senescence. It can be further aided by the transcriptional repression of proliferation-associated genes by the action of HP1γ, HMGA, and DNMT proteins to produce a repressive chromatin environment. Therefore, senescence has been suggested to functions as a natural brake for tumor development and plays a critical role in tumor suppression and aging.
An in vitro senescence model has been established by using K562 cells treated with 50 nM doxorubicin (DOX). Since p53 and p16 are homozygously deleted in the K562 cells, the DOX-induced senescence in K562 cells ought to be independent of p53 and p16-pRb pathways. Indeed, no change in the expression of the typical senescence-associated premalignant cell markers in the DOX-induced senescent K562 cells was found. MicroRNA profiling revealed upregulated miR-375 in DOX-induced senescent K562 cells. Treatment with miR-375 inhibitor was able to reverse the proliferation ability suppressed by DOX (p<0.05) and overexpression of miR-375 suppressed the normal proliferation of K562 cells. Upregulated miR-375 expression was associated with downregulated expression of 14-3-3zeta and SP1 genes. Autophagy was also investigated since DOX treatment was able to induce cells entering senescence and eventually lead to cell death. Among the 24 human autophagy-related genes examined, a 12-fold increase of ATG9B at day 4 and a 20-fold increase of ATG18 at day 2 after DOX treatment were noted.
This study has demonstrated that in the absence of p53 and p16, the induction of senescence by DOX was associated with upregulation of miR-375 and autophagy initiation. The anti-proliferative function of miR-375 is possibly exerted, at least in part, by targeting 14-3-3zeta and SP1 genes.</description><subject>14-3-3 Proteins - genetics</subject><subject>Aging</subject><subject>Aging (natural)</subject><subject>Analysis</subject><subject>Anthracyclines</subject><subject>Apoptosis</subject><subject>Autophagy</subject><subject>Autophagy - drug effects</subject><subject>Biology</subject><subject>Cell cycle</subject><subject>Cell death</subject><subject>Cell growth</subject><subject>Cell proliferation</subject><subject>Cellular Senescence - drug effects</subject><subject>Cellular Senescence - genetics</subject><subject>Cellular Senescence - physiology</subject><subject>Cervical cancer</subject><subject>Chromatin</subject><subject>Chromosomal proteins</subject><subject>Dehydrogenases</subject><subject>Development and progression</subject><subject>Doxorubicin</subject><subject>Doxorubicin - pharmacology</subject><subject>E2F protein</subject><subject>Esophageal cancer</subject><subject>Gastric cancer</subject><subject>Gene expression</subject><subject>Gene silencing</subject><subject>Genes</subject><subject>Genes, p16</subject><subject>Genes, p53</subject><subject>Genetic aspects</subject><subject>Hematology</subject><subject>Hospitals</subject><subject>Humans</subject><subject>Insulin-like growth factors</subject><subject>Internal medicine</subject><subject>K562 Cells</subject><subject>Kinases</subject><subject>Liver cancer</subject><subject>Medicine</subject><subject>Metastasis</subject><subject>MicroRNA</subject><subject>MicroRNAs</subject><subject>MicroRNAs - genetics</subject><subject>miRNA</subject><subject>Models, Biological</subject><subject>Morphology</subject><subject>Oncology</subject><subject>p53 Protein</subject><subject>Phagocytosis</subject><subject>Proteins</subject><subject>Ribonucleic acid</subject><subject>RNA</subject><subject>Senescence</subject><subject>Sp1 protein</subject><subject>Sp1 Transcription Factor - genetics</subject><subject>Stomach cancer</subject><subject>Transcription (Genetics)</subject><subject>Transcription factors</subject><subject>Tumor proteins</subject><subject>Tumor suppression</subject><subject>Up-Regulation - drug effects</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqNkl2L1DAYhYso7rr6D0QDguDFjPlOeyMsix-DCwvrx214m6QzGTrNmLS6c-VfN7PTXaagILloePuck-RwiuI5wXPCFHm7DkPsoJ1vQ-fmGDNFsXhQnJKK0ZmkmD082p8UT1JaYyxYKeXj4oRSiSUT5LT4vejsYHofOhQaZFzbDi1ElFznknGdcajeIRtuQhxqb3yHfEKQUjAeemfRL9-v0LCNbpll-8HGX8-YEgg6i_yxNQx92K5guctj9FlIentYelo8aqBN7tn4PSu-fXj_9eLT7PLq4-Li_HJmZEX7GREWVzWRRDAwrLZNfhqoitWcVXUlFBXKEOBKlsKWllvHVNlwBxy7SgAv2Vnx8uC7bUPSY3ZJE0a5xEoplonFgbAB1nob_QbiTgfw-nYQ4lJD7L1pnabcCtxgWjYKc8IYOCCmAUZdpSQxMnu9G08b6o2zOcg-Qjsxnf7p_Eovw0_NmMC83Bu8Gg1i-DG41P_jyiO1hHwr3zUhm5mNT0afc6UIkaLkmZr_hcrLuo03uT2Nz_OJ4M1EkJne3fRLGFLSiy_X_89efZ-yr4_YlYO2X6XQDvuKpCnID6CJIaXomvvkCNb78t-loffl12P5s-zFcer3oru2sz9aGP7s</recordid><startdate>20120511</startdate><enddate>20120511</enddate><creator>Yang, Ming-Yu</creator><creator>Lin, Pai-Mei</creator><creator>Liu, Yi-Chang</creator><creator>Hsiao, Hui-Hua</creator><creator>Yang, Wen-Chi</creator><creator>Hsu, Jui-Feng</creator><creator>Hsu, Cheng-Ming</creator><creator>Lin, Sheng-Fung</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><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>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20120511</creationdate><title>Induction of cellular senescence by doxorubicin is associated with upregulated miR-375 and induction of autophagy in K562 cells</title><author>Yang, Ming-Yu ; Lin, Pai-Mei ; Liu, Yi-Chang ; Hsiao, Hui-Hua ; Yang, Wen-Chi ; Hsu, Jui-Feng ; Hsu, Cheng-Ming ; Lin, Sheng-Fung</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-15d09b16153ac3bdf193a793b439b957257c1a47685d8d4de378f4ea40e95a483</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>14-3-3 Proteins - 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Upregulated p16, p53, and p21 expression and silencing of E2F target genes have been characterized to promote the establishment of senescence. It can be further aided by the transcriptional repression of proliferation-associated genes by the action of HP1γ, HMGA, and DNMT proteins to produce a repressive chromatin environment. Therefore, senescence has been suggested to functions as a natural brake for tumor development and plays a critical role in tumor suppression and aging.
An in vitro senescence model has been established by using K562 cells treated with 50 nM doxorubicin (DOX). Since p53 and p16 are homozygously deleted in the K562 cells, the DOX-induced senescence in K562 cells ought to be independent of p53 and p16-pRb pathways. Indeed, no change in the expression of the typical senescence-associated premalignant cell markers in the DOX-induced senescent K562 cells was found. MicroRNA profiling revealed upregulated miR-375 in DOX-induced senescent K562 cells. Treatment with miR-375 inhibitor was able to reverse the proliferation ability suppressed by DOX (p<0.05) and overexpression of miR-375 suppressed the normal proliferation of K562 cells. Upregulated miR-375 expression was associated with downregulated expression of 14-3-3zeta and SP1 genes. Autophagy was also investigated since DOX treatment was able to induce cells entering senescence and eventually lead to cell death. Among the 24 human autophagy-related genes examined, a 12-fold increase of ATG9B at day 4 and a 20-fold increase of ATG18 at day 2 after DOX treatment were noted.
This study has demonstrated that in the absence of p53 and p16, the induction of senescence by DOX was associated with upregulation of miR-375 and autophagy initiation. The anti-proliferative function of miR-375 is possibly exerted, at least in part, by targeting 14-3-3zeta and SP1 genes.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>22606351</pmid><doi>10.1371/journal.pone.0037205</doi><tpages>e37205</tpages><oa>free_for_read</oa></addata></record> |
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| recordid | cdi_plos_journals_1324607773 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Public Library of Science (PLoS); PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | 14-3-3 Proteins - genetics Aging Aging (natural) Analysis Anthracyclines Apoptosis Autophagy Autophagy - drug effects Biology Cell cycle Cell death Cell growth Cell proliferation Cellular Senescence - drug effects Cellular Senescence - genetics Cellular Senescence - physiology Cervical cancer Chromatin Chromosomal proteins Dehydrogenases Development and progression Doxorubicin Doxorubicin - pharmacology E2F protein Esophageal cancer Gastric cancer Gene expression Gene silencing Genes Genes, p16 Genes, p53 Genetic aspects Hematology Hospitals Humans Insulin-like growth factors Internal medicine K562 Cells Kinases Liver cancer Medicine Metastasis MicroRNA MicroRNAs MicroRNAs - genetics miRNA Models, Biological Morphology Oncology p53 Protein Phagocytosis Proteins Ribonucleic acid RNA Senescence Sp1 protein Sp1 Transcription Factor - genetics Stomach cancer Transcription (Genetics) Transcription factors Tumor proteins Tumor suppression Up-Regulation - drug effects |
| title | Induction of cellular senescence by doxorubicin is associated with upregulated miR-375 and induction of autophagy in K562 cells |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-25T14%3A24%3A56IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Induction%20of%20cellular%20senescence%20by%20doxorubicin%20is%20associated%20with%20upregulated%20miR-375%20and%20induction%20of%20autophagy%20in%20K562%20cells&rft.jtitle=PloS%20one&rft.au=Yang,%20Ming-Yu&rft.date=2012-05-11&rft.volume=7&rft.issue=5&rft.spage=e37205&rft.pages=e37205-&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0037205&rft_dat=%3Cgale_plos_%3EA477116584%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1324607773&rft_id=info:pmid/22606351&rft_galeid=A477116584&rft_doaj_id=oai_doaj_org_article_24d50f028f704133aea1cfa32e9761c6&rfr_iscdi=true |