Loss of PTEN-assisted G2/M checkpoint impedes homologous recombination repair and enhances radio-curability and PARP inhibitor treatment response in prostate cancer
Here we report that PTEN contributes to DNA double-strand break (DSB) repair via homologous recombination (HR), as evidenced by (i) inhibition of HR in a reporter plasmid assay, (ii) enhanced sensitivity to mitomycin-C or olaparib and (iii) reduced RAD51 loading at IR-induced DSBs upon PTEN knockdow...
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| creator | Mansour, W. Y. Tennstedt, P. Volquardsen, J. Oing, C. Kluth, M. Hube-Magg, C. Borgmann, K. Simon, R. Petersen, C. Dikomey, E. Rothkamm, K. |
| description | Here we report that PTEN contributes to DNA double-strand break (DSB) repair via homologous recombination (HR), as evidenced by (i) inhibition of HR in a reporter plasmid assay, (ii) enhanced sensitivity to mitomycin-C or olaparib and (iii) reduced RAD51 loading at IR-induced DSBs upon PTEN knockdown. No association was observed between PTEN-status and RAD51 expression either
in-vitro
or
in-vivo
in a tissue microarray of 1500 PTEN-deficient prostate cancer (PC) samples. PTEN depletion and sustained activation of AKT sequestered CHK1 in the cytoplasm, thus impairing the G2/M-checkpoint after irradiation. Consistently, AKT inhibition recovered the G2/M-checkpoint and restored HR efficiency in PTEN-depleted cells. We show that, although
PTEN
loss correlates with a worse prognosis, it may predict for improved response of PC patients to radiotherapy. Further, we provide evidence for the use of PTEN as a biomarker for predicting the response to PARP inhibitors as radiosensitizing agents in prostate cancer. Collectively, these data implicate PTEN in maintaining genomic stability by delaying G2/M-phase progression of damaged cells, thus allowing time for DSB repair by HR. Furthermore, we identify PTEN-status in PC as a putative predictor of (i) radiotherapy response and (ii) response to treatment with PARP inhibitor alone or combined with radiotherapy. |
| doi_str_mv | 10.1038/s41598-018-22289-7 |
| format | Article |
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in-vitro
or
in-vivo
in a tissue microarray of 1500 PTEN-deficient prostate cancer (PC) samples. PTEN depletion and sustained activation of AKT sequestered CHK1 in the cytoplasm, thus impairing the G2/M-checkpoint after irradiation. Consistently, AKT inhibition recovered the G2/M-checkpoint and restored HR efficiency in PTEN-depleted cells. We show that, although
PTEN
loss correlates with a worse prognosis, it may predict for improved response of PC patients to radiotherapy. Further, we provide evidence for the use of PTEN as a biomarker for predicting the response to PARP inhibitors as radiosensitizing agents in prostate cancer. Collectively, these data implicate PTEN in maintaining genomic stability by delaying G2/M-phase progression of damaged cells, thus allowing time for DSB repair by HR. Furthermore, we identify PTEN-status in PC as a putative predictor of (i) radiotherapy response and (ii) response to treatment with PARP inhibitor alone or combined with radiotherapy.</description><identifier>ISSN: 2045-2322</identifier><identifier>EISSN: 2045-2322</identifier><identifier>DOI: 10.1038/s41598-018-22289-7</identifier><identifier>PMID: 29500400</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13 ; 13/1 ; 13/106 ; 13/109 ; 13/31 ; 13/44 ; 13/51 ; 13/89 ; 14 ; 14/19 ; 14/32 ; 14/34 ; 38 ; 631/45/147 ; 631/67/589/466 ; AKT protein ; CHK1 protein ; Cytoplasm ; DNA damage ; DNA microarrays ; DNA repair ; Double-strand break repair ; Homologous recombination ; Homologous recombination repair ; Humanities and Social Sciences ; Irradiation ; Mitomycin C ; multidisciplinary ; Poly(ADP-ribose) polymerase ; Prostate cancer ; PTEN protein ; Radiation therapy ; Science ; Science (multidisciplinary) ; Targeted cancer therapy</subject><ispartof>Scientific reports, 2018-03, Vol.8 (1), p.3947-12, Article 3947</ispartof><rights>The Author(s) 2018</rights><rights>2018. 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-c474t-153e85ff79976b6ded9111f755659a3bb08b8fae3455f5a604a81d4ba2f922423</citedby><cites>FETCH-LOGICAL-c474t-153e85ff79976b6ded9111f755659a3bb08b8fae3455f5a604a81d4ba2f922423</cites><orcidid>0000-0001-7414-5729</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/PMC5834544/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834544/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,27901,27902,41096,42165,51551,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29500400$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Mansour, W. Y.</creatorcontrib><creatorcontrib>Tennstedt, P.</creatorcontrib><creatorcontrib>Volquardsen, J.</creatorcontrib><creatorcontrib>Oing, C.</creatorcontrib><creatorcontrib>Kluth, M.</creatorcontrib><creatorcontrib>Hube-Magg, C.</creatorcontrib><creatorcontrib>Borgmann, K.</creatorcontrib><creatorcontrib>Simon, R.</creatorcontrib><creatorcontrib>Petersen, C.</creatorcontrib><creatorcontrib>Dikomey, E.</creatorcontrib><creatorcontrib>Rothkamm, K.</creatorcontrib><title>Loss of PTEN-assisted G2/M checkpoint impedes homologous recombination repair and enhances radio-curability and PARP inhibitor treatment response in prostate cancer</title><title>Scientific reports</title><addtitle>Sci Rep</addtitle><addtitle>Sci Rep</addtitle><description>Here we report that PTEN contributes to DNA double-strand break (DSB) repair via homologous recombination (HR), as evidenced by (i) inhibition of HR in a reporter plasmid assay, (ii) enhanced sensitivity to mitomycin-C or olaparib and (iii) reduced RAD51 loading at IR-induced DSBs upon PTEN knockdown. No association was observed between PTEN-status and RAD51 expression either
in-vitro
or
in-vivo
in a tissue microarray of 1500 PTEN-deficient prostate cancer (PC) samples. PTEN depletion and sustained activation of AKT sequestered CHK1 in the cytoplasm, thus impairing the G2/M-checkpoint after irradiation. Consistently, AKT inhibition recovered the G2/M-checkpoint and restored HR efficiency in PTEN-depleted cells. We show that, although
PTEN
loss correlates with a worse prognosis, it may predict for improved response of PC patients to radiotherapy. Further, we provide evidence for the use of PTEN as a biomarker for predicting the response to PARP inhibitors as radiosensitizing agents in prostate cancer. Collectively, these data implicate PTEN in maintaining genomic stability by delaying G2/M-phase progression of damaged cells, thus allowing time for DSB repair by HR. Furthermore, we identify PTEN-status in PC as a putative predictor of (i) radiotherapy response and (ii) response to treatment with PARP inhibitor alone or combined with radiotherapy.</description><subject>13</subject><subject>13/1</subject><subject>13/106</subject><subject>13/109</subject><subject>13/31</subject><subject>13/44</subject><subject>13/51</subject><subject>13/89</subject><subject>14</subject><subject>14/19</subject><subject>14/32</subject><subject>14/34</subject><subject>38</subject><subject>631/45/147</subject><subject>631/67/589/466</subject><subject>AKT protein</subject><subject>CHK1 protein</subject><subject>Cytoplasm</subject><subject>DNA damage</subject><subject>DNA microarrays</subject><subject>DNA repair</subject><subject>Double-strand break repair</subject><subject>Homologous recombination</subject><subject>Homologous recombination repair</subject><subject>Humanities and Social Sciences</subject><subject>Irradiation</subject><subject>Mitomycin C</subject><subject>multidisciplinary</subject><subject>Poly(ADP-ribose) polymerase</subject><subject>Prostate cancer</subject><subject>PTEN protein</subject><subject>Radiation therapy</subject><subject>Science</subject><subject>Science (multidisciplinary)</subject><subject>Targeted cancer therapy</subject><issn>2045-2322</issn><issn>2045-2322</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>BENPR</sourceid><recordid>eNp9Us1uFSEYJUZjm2tfwIUhceNmWmDgDmxMmqbWJle9MXVNGOabO9QZGIFp0vfxQaW9tVYXsgFyzne-v4PQa0qOKanlSeJUKFkRKivGmFRV8wwdMsJFxWrGnj95H6CjlK5JOYIpTtVLdMCUIIQTcoh-bkJKOPR4e3X-uTIpuZShwxfs5BO2A9jvc3A-YzfN0EHCQ5jCGHZhSTiCDVPrvMku-PKbjYvY-A6DH4y3hRxN50Jll2haN7p8e49uT79usfODa10OEecIJk9QUkRIc_AJCojnGFI2GbC9U4qv0IvejAmOHu4V-vbh_OrsY7X5cnF5drqpLG94rqioQYq-b5Rq1u26g05RSvtGiLVQpm5bIlvZG6i5EL0wa8KNpB1vDesVY5zVK_R-rzsv7QSdLWVFM-o5usnEWx2M038j3g16F260kEWT8yLw7kEghh8LpKwnlyyMo_FQZqYZKbtraqpIob79h3odluhLe4VFlGwkKaorxPYsWyaSIvSPxVCi73yg9z7QxQf63ge6KUFvnrbxGPJ764VQ7wmpQH4H8U_u_8j-AloLwR0</recordid><startdate>20180302</startdate><enddate>20180302</enddate><creator>Mansour, W. 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Y. ; Tennstedt, P. ; Volquardsen, J. ; Oing, C. ; Kluth, M. ; Hube-Magg, C. ; Borgmann, K. ; Simon, R. ; Petersen, C. ; Dikomey, E. ; Rothkamm, K.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c474t-153e85ff79976b6ded9111f755659a3bb08b8fae3455f5a604a81d4ba2f922423</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>13</topic><topic>13/1</topic><topic>13/106</topic><topic>13/109</topic><topic>13/31</topic><topic>13/44</topic><topic>13/51</topic><topic>13/89</topic><topic>14</topic><topic>14/19</topic><topic>14/32</topic><topic>14/34</topic><topic>38</topic><topic>631/45/147</topic><topic>631/67/589/466</topic><topic>AKT protein</topic><topic>CHK1 protein</topic><topic>Cytoplasm</topic><topic>DNA damage</topic><topic>DNA microarrays</topic><topic>DNA repair</topic><topic>Double-strand break repair</topic><topic>Homologous recombination</topic><topic>Homologous recombination repair</topic><topic>Humanities and Social Sciences</topic><topic>Irradiation</topic><topic>Mitomycin C</topic><topic>multidisciplinary</topic><topic>Poly(ADP-ribose) polymerase</topic><topic>Prostate cancer</topic><topic>PTEN protein</topic><topic>Radiation therapy</topic><topic>Science</topic><topic>Science (multidisciplinary)</topic><topic>Targeted cancer therapy</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Mansour, W. Y.</creatorcontrib><creatorcontrib>Tennstedt, P.</creatorcontrib><creatorcontrib>Volquardsen, J.</creatorcontrib><creatorcontrib>Oing, C.</creatorcontrib><creatorcontrib>Kluth, M.</creatorcontrib><creatorcontrib>Hube-Magg, C.</creatorcontrib><creatorcontrib>Borgmann, K.</creatorcontrib><creatorcontrib>Simon, R.</creatorcontrib><creatorcontrib>Petersen, C.</creatorcontrib><creatorcontrib>Dikomey, E.</creatorcontrib><creatorcontrib>Rothkamm, K.</creatorcontrib><collection>Springer Nature OA Free Journals</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>Medical 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 Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection (ProQuest)</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>Medical Database</collection><collection>Science Database</collection><collection>Biological Science Database</collection><collection>ProQuest Central (New)</collection><collection>ProQuest One Academic (New)</collection><collection>Publicly Available Content Database</collection><collection>ProQuest Health & Medical Research Collection</collection><collection>ProQuest One Academic Middle East (New)</collection><collection>ProQuest One Health & Nursing</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Applied & Life Sciences</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>Scientific reports</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Mansour, W. Y.</au><au>Tennstedt, P.</au><au>Volquardsen, J.</au><au>Oing, C.</au><au>Kluth, M.</au><au>Hube-Magg, C.</au><au>Borgmann, K.</au><au>Simon, R.</au><au>Petersen, C.</au><au>Dikomey, E.</au><au>Rothkamm, K.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Loss of PTEN-assisted G2/M checkpoint impedes homologous recombination repair and enhances radio-curability and PARP inhibitor treatment response in prostate cancer</atitle><jtitle>Scientific reports</jtitle><stitle>Sci Rep</stitle><addtitle>Sci Rep</addtitle><date>2018-03-02</date><risdate>2018</risdate><volume>8</volume><issue>1</issue><spage>3947</spage><epage>12</epage><pages>3947-12</pages><artnum>3947</artnum><issn>2045-2322</issn><eissn>2045-2322</eissn><abstract>Here we report that PTEN contributes to DNA double-strand break (DSB) repair via homologous recombination (HR), as evidenced by (i) inhibition of HR in a reporter plasmid assay, (ii) enhanced sensitivity to mitomycin-C or olaparib and (iii) reduced RAD51 loading at IR-induced DSBs upon PTEN knockdown. No association was observed between PTEN-status and RAD51 expression either
in-vitro
or
in-vivo
in a tissue microarray of 1500 PTEN-deficient prostate cancer (PC) samples. PTEN depletion and sustained activation of AKT sequestered CHK1 in the cytoplasm, thus impairing the G2/M-checkpoint after irradiation. Consistently, AKT inhibition recovered the G2/M-checkpoint and restored HR efficiency in PTEN-depleted cells. We show that, although
PTEN
loss correlates with a worse prognosis, it may predict for improved response of PC patients to radiotherapy. Further, we provide evidence for the use of PTEN as a biomarker for predicting the response to PARP inhibitors as radiosensitizing agents in prostate cancer. Collectively, these data implicate PTEN in maintaining genomic stability by delaying G2/M-phase progression of damaged cells, thus allowing time for DSB repair by HR. Furthermore, we identify PTEN-status in PC as a putative predictor of (i) radiotherapy response and (ii) response to treatment with PARP inhibitor alone or combined with radiotherapy.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>29500400</pmid><doi>10.1038/s41598-018-22289-7</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0001-7414-5729</orcidid><oa>free_for_read</oa></addata></record> |
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| source | Nature Free; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Alma/SFX Local Collection; Free Full-Text Journals in Chemistry; Springer Nature OA Free Journals |
| subjects | 13 13/1 13/106 13/109 13/31 13/44 13/51 13/89 14 14/19 14/32 14/34 38 631/45/147 631/67/589/466 AKT protein CHK1 protein Cytoplasm DNA damage DNA microarrays DNA repair Double-strand break repair Homologous recombination Homologous recombination repair Humanities and Social Sciences Irradiation Mitomycin C multidisciplinary Poly(ADP-ribose) polymerase Prostate cancer PTEN protein Radiation therapy Science Science (multidisciplinary) Targeted cancer therapy |
| title | Loss of PTEN-assisted G2/M checkpoint impedes homologous recombination repair and enhances radio-curability and PARP inhibitor treatment response in prostate cancer |
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