Rapamycin-induced miR-21 promotes mitochondrial homeostasis and adaptation in mTORC1 activated cells
mTORC1 hyperactivation drives the multi-organ hamartomatous disease tuberous sclerosis complex (TSC). Rapamycin inhibits mTORC1, inducing partial tumor responses; however, the tumors regrow following treatment cessation. We discovered that the oncogenic miRNA, miR-21, is increased in Tsc2-deficient...
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| creator | Lam, Hilaire C Liu, Heng-Jia Baglini, Christian V Filippakis, Harilaos Alesi, Nicola Nijmeh, Julie Du, Heng Lope, Alicia Llorente Cottrill, Katherine A Handen, Adam Asara, John M Kwiatkowski, David J Ben-Sahra, Issam Oldham, William M Chan, Stephen Y Henske, Elizabeth P |
| description | mTORC1 hyperactivation drives the multi-organ hamartomatous disease tuberous sclerosis complex (TSC). Rapamycin inhibits mTORC1, inducing partial tumor responses; however, the tumors regrow following treatment cessation. We discovered that the oncogenic miRNA, miR-21, is increased in Tsc2-deficient cells and, surprisingly, further increased by rapamycin. To determine the impact of miR-21 in TSC, we inhibited miR-21
. miR-21 inhibition significantly repressed the tumorigenic potential of Tsc2-deficient cells and increased apoptosis sensitivity. Tsc2-deficient cells' clonogenic and anchorage independent growth were reduced by ∼50% ( |
| doi_str_mv | 10.18632/oncotarget.19947 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5630288</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1951417365</sourcerecordid><originalsourceid>FETCH-LOGICAL-c356t-f0aae4d16590b8d12d66d82c3da15bcf23d898199df6b0b8b9d929df6985a34d3</originalsourceid><addsrcrecordid>eNpVUU1LxDAQDaK4ov4AL9Kjl65N0nSTiyCLX7CwsKznME1SN9ImNUkX_Pd2_VznMvOYN29meAhd4GKKeUXJtXfKJwgvJk2xEOXsAJ1gUYqcMEYP9-oJOo_xtRiDlTNOxDGaEFEQQTk_QXoFPXTvyrrcOj0oo7POrnKCsz74zicTR5y82ning4U22_jO-Jgg2piB0xlo6BMk611mXdatl6s5zkAlu4U0iinTtvEMHTXQRnP-nU_R8_3dev6YL5YPT_PbRa4oq1LeFACm1Lhioqi5xkRXleZEUQ2Y1aohVHPBx191U9UjoxZakB0QnAEtNT1FN1-6_VB3RivjUoBW9sF2EN6lByv_d5zdyBe_layiBeF8FLj6Fgj-bTAxyc7G3QvgjB-ixILhEs9oxUYq_qKq4GMMpvldgwv5aZD8M0h-GjTOXO7f9zvxYwf9AMQHkaU</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1951417365</pqid></control><display><type>article</type><title>Rapamycin-induced miR-21 promotes mitochondrial homeostasis and adaptation in mTORC1 activated cells</title><source>EZB-FREE-00999 freely available EZB journals</source><source>PubMed Central</source><source>Free E- Journals</source><source>PubMed Central Open Access</source><creator>Lam, Hilaire C ; Liu, Heng-Jia ; Baglini, Christian V ; Filippakis, Harilaos ; Alesi, Nicola ; Nijmeh, Julie ; Du, Heng ; Lope, Alicia Llorente ; Cottrill, Katherine A ; Handen, Adam ; Asara, John M ; Kwiatkowski, David J ; Ben-Sahra, Issam ; Oldham, William M ; Chan, Stephen Y ; Henske, Elizabeth P</creator><creatorcontrib>Lam, Hilaire C ; Liu, Heng-Jia ; Baglini, Christian V ; Filippakis, Harilaos ; Alesi, Nicola ; Nijmeh, Julie ; Du, Heng ; Lope, Alicia Llorente ; Cottrill, Katherine A ; Handen, Adam ; Asara, John M ; Kwiatkowski, David J ; Ben-Sahra, Issam ; Oldham, William M ; Chan, Stephen Y ; Henske, Elizabeth P</creatorcontrib><description>mTORC1 hyperactivation drives the multi-organ hamartomatous disease tuberous sclerosis complex (TSC). Rapamycin inhibits mTORC1, inducing partial tumor responses; however, the tumors regrow following treatment cessation. We discovered that the oncogenic miRNA, miR-21, is increased in Tsc2-deficient cells and, surprisingly, further increased by rapamycin. To determine the impact of miR-21 in TSC, we inhibited miR-21
. miR-21 inhibition significantly repressed the tumorigenic potential of Tsc2-deficient cells and increased apoptosis sensitivity. Tsc2-deficient cells' clonogenic and anchorage independent growth were reduced by ∼50% (
<0.01) and ∼75% (
<0.0001), respectively, and combined rapamycin treatment decreased soft agar growth by ∼90% (
<0.0001). miR-21 inhibition also increased sensitivity to apoptosis. Through a network biology-driven integration of RNAseq data, we discovered that miR-21 promotes mitochondrial adaptation and homeostasis in Tsc2-deficient cells. miR-21 inhibition reduced mitochondrial polarization and function in Tsc2-deficient cells, with and without co-treatment with rapamycin. Importantly, miR-21 inhibition limited Tsc2-deficient tumor growth
, reducing tumor size by approximately 3-fold (
<0.0001). When combined with rapamcyin, miR-21 inhibition showed even more striking efficacy, both during treatment and after treatment cessation, with a 4-fold increase in median survival following rapamycin cessation (
=0.0008). We conclude that miR-21 promotes mTORC1-driven tumorigenesis
a mechanism that involves the mitochondria, and that miR-21 is a potential therapeutic target for TSC-associated hamartomas and other mTORC1-driven tumors, with the potential for synergistic efficacy when combined with rapalogs.</description><identifier>ISSN: 1949-2553</identifier><identifier>EISSN: 1949-2553</identifier><identifier>DOI: 10.18632/oncotarget.19947</identifier><identifier>PMID: 29029388</identifier><language>eng</language><publisher>United States: Impact Journals LLC</publisher><subject>Priority Research Paper</subject><ispartof>Oncotarget, 2017-09, Vol.8 (39), p.64714-64727</ispartof><rights>Copyright: © 2017 Lam et al. 2017</rights><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c356t-f0aae4d16590b8d12d66d82c3da15bcf23d898199df6b0b8b9d929df6985a34d3</citedby><cites>FETCH-LOGICAL-c356t-f0aae4d16590b8d12d66d82c3da15bcf23d898199df6b0b8b9d929df6985a34d3</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/PMC5630288/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5630288/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29029388$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lam, Hilaire C</creatorcontrib><creatorcontrib>Liu, Heng-Jia</creatorcontrib><creatorcontrib>Baglini, Christian V</creatorcontrib><creatorcontrib>Filippakis, Harilaos</creatorcontrib><creatorcontrib>Alesi, Nicola</creatorcontrib><creatorcontrib>Nijmeh, Julie</creatorcontrib><creatorcontrib>Du, Heng</creatorcontrib><creatorcontrib>Lope, Alicia Llorente</creatorcontrib><creatorcontrib>Cottrill, Katherine A</creatorcontrib><creatorcontrib>Handen, Adam</creatorcontrib><creatorcontrib>Asara, John M</creatorcontrib><creatorcontrib>Kwiatkowski, David J</creatorcontrib><creatorcontrib>Ben-Sahra, Issam</creatorcontrib><creatorcontrib>Oldham, William M</creatorcontrib><creatorcontrib>Chan, Stephen Y</creatorcontrib><creatorcontrib>Henske, Elizabeth P</creatorcontrib><title>Rapamycin-induced miR-21 promotes mitochondrial homeostasis and adaptation in mTORC1 activated cells</title><title>Oncotarget</title><addtitle>Oncotarget</addtitle><description>mTORC1 hyperactivation drives the multi-organ hamartomatous disease tuberous sclerosis complex (TSC). Rapamycin inhibits mTORC1, inducing partial tumor responses; however, the tumors regrow following treatment cessation. We discovered that the oncogenic miRNA, miR-21, is increased in Tsc2-deficient cells and, surprisingly, further increased by rapamycin. To determine the impact of miR-21 in TSC, we inhibited miR-21
. miR-21 inhibition significantly repressed the tumorigenic potential of Tsc2-deficient cells and increased apoptosis sensitivity. Tsc2-deficient cells' clonogenic and anchorage independent growth were reduced by ∼50% (
<0.01) and ∼75% (
<0.0001), respectively, and combined rapamycin treatment decreased soft agar growth by ∼90% (
<0.0001). miR-21 inhibition also increased sensitivity to apoptosis. Through a network biology-driven integration of RNAseq data, we discovered that miR-21 promotes mitochondrial adaptation and homeostasis in Tsc2-deficient cells. miR-21 inhibition reduced mitochondrial polarization and function in Tsc2-deficient cells, with and without co-treatment with rapamycin. Importantly, miR-21 inhibition limited Tsc2-deficient tumor growth
, reducing tumor size by approximately 3-fold (
<0.0001). When combined with rapamcyin, miR-21 inhibition showed even more striking efficacy, both during treatment and after treatment cessation, with a 4-fold increase in median survival following rapamycin cessation (
=0.0008). We conclude that miR-21 promotes mTORC1-driven tumorigenesis
a mechanism that involves the mitochondria, and that miR-21 is a potential therapeutic target for TSC-associated hamartomas and other mTORC1-driven tumors, with the potential for synergistic efficacy when combined with rapalogs.</description><subject>Priority Research Paper</subject><issn>1949-2553</issn><issn>1949-2553</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><recordid>eNpVUU1LxDAQDaK4ov4AL9Kjl65N0nSTiyCLX7CwsKznME1SN9ImNUkX_Pd2_VznMvOYN29meAhd4GKKeUXJtXfKJwgvJk2xEOXsAJ1gUYqcMEYP9-oJOo_xtRiDlTNOxDGaEFEQQTk_QXoFPXTvyrrcOj0oo7POrnKCsz74zicTR5y82ning4U22_jO-Jgg2piB0xlo6BMk611mXdatl6s5zkAlu4U0iinTtvEMHTXQRnP-nU_R8_3dev6YL5YPT_PbRa4oq1LeFACm1Lhioqi5xkRXleZEUQ2Y1aohVHPBx191U9UjoxZakB0QnAEtNT1FN1-6_VB3RivjUoBW9sF2EN6lByv_d5zdyBe_layiBeF8FLj6Fgj-bTAxyc7G3QvgjB-ixILhEs9oxUYq_qKq4GMMpvldgwv5aZD8M0h-GjTOXO7f9zvxYwf9AMQHkaU</recordid><startdate>20170912</startdate><enddate>20170912</enddate><creator>Lam, Hilaire C</creator><creator>Liu, Heng-Jia</creator><creator>Baglini, Christian V</creator><creator>Filippakis, Harilaos</creator><creator>Alesi, Nicola</creator><creator>Nijmeh, Julie</creator><creator>Du, Heng</creator><creator>Lope, Alicia Llorente</creator><creator>Cottrill, Katherine A</creator><creator>Handen, Adam</creator><creator>Asara, John M</creator><creator>Kwiatkowski, David J</creator><creator>Ben-Sahra, Issam</creator><creator>Oldham, William M</creator><creator>Chan, Stephen Y</creator><creator>Henske, Elizabeth P</creator><general>Impact Journals LLC</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20170912</creationdate><title>Rapamycin-induced miR-21 promotes mitochondrial homeostasis and adaptation in mTORC1 activated cells</title><author>Lam, Hilaire C ; Liu, Heng-Jia ; Baglini, Christian V ; Filippakis, Harilaos ; Alesi, Nicola ; Nijmeh, Julie ; Du, Heng ; Lope, Alicia Llorente ; Cottrill, Katherine A ; Handen, Adam ; Asara, John M ; Kwiatkowski, David J ; Ben-Sahra, Issam ; Oldham, William M ; Chan, Stephen Y ; Henske, Elizabeth P</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c356t-f0aae4d16590b8d12d66d82c3da15bcf23d898199df6b0b8b9d929df6985a34d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Priority Research Paper</topic><toplevel>online_resources</toplevel><creatorcontrib>Lam, Hilaire C</creatorcontrib><creatorcontrib>Liu, Heng-Jia</creatorcontrib><creatorcontrib>Baglini, Christian V</creatorcontrib><creatorcontrib>Filippakis, Harilaos</creatorcontrib><creatorcontrib>Alesi, Nicola</creatorcontrib><creatorcontrib>Nijmeh, Julie</creatorcontrib><creatorcontrib>Du, Heng</creatorcontrib><creatorcontrib>Lope, Alicia Llorente</creatorcontrib><creatorcontrib>Cottrill, Katherine A</creatorcontrib><creatorcontrib>Handen, Adam</creatorcontrib><creatorcontrib>Asara, John M</creatorcontrib><creatorcontrib>Kwiatkowski, David J</creatorcontrib><creatorcontrib>Ben-Sahra, Issam</creatorcontrib><creatorcontrib>Oldham, William M</creatorcontrib><creatorcontrib>Chan, Stephen Y</creatorcontrib><creatorcontrib>Henske, Elizabeth P</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Oncotarget</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lam, Hilaire C</au><au>Liu, Heng-Jia</au><au>Baglini, Christian V</au><au>Filippakis, Harilaos</au><au>Alesi, Nicola</au><au>Nijmeh, Julie</au><au>Du, Heng</au><au>Lope, Alicia Llorente</au><au>Cottrill, Katherine A</au><au>Handen, Adam</au><au>Asara, John M</au><au>Kwiatkowski, David J</au><au>Ben-Sahra, Issam</au><au>Oldham, William M</au><au>Chan, Stephen Y</au><au>Henske, Elizabeth P</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Rapamycin-induced miR-21 promotes mitochondrial homeostasis and adaptation in mTORC1 activated cells</atitle><jtitle>Oncotarget</jtitle><addtitle>Oncotarget</addtitle><date>2017-09-12</date><risdate>2017</risdate><volume>8</volume><issue>39</issue><spage>64714</spage><epage>64727</epage><pages>64714-64727</pages><issn>1949-2553</issn><eissn>1949-2553</eissn><abstract>mTORC1 hyperactivation drives the multi-organ hamartomatous disease tuberous sclerosis complex (TSC). Rapamycin inhibits mTORC1, inducing partial tumor responses; however, the tumors regrow following treatment cessation. We discovered that the oncogenic miRNA, miR-21, is increased in Tsc2-deficient cells and, surprisingly, further increased by rapamycin. To determine the impact of miR-21 in TSC, we inhibited miR-21
. miR-21 inhibition significantly repressed the tumorigenic potential of Tsc2-deficient cells and increased apoptosis sensitivity. Tsc2-deficient cells' clonogenic and anchorage independent growth were reduced by ∼50% (
<0.01) and ∼75% (
<0.0001), respectively, and combined rapamycin treatment decreased soft agar growth by ∼90% (
<0.0001). miR-21 inhibition also increased sensitivity to apoptosis. Through a network biology-driven integration of RNAseq data, we discovered that miR-21 promotes mitochondrial adaptation and homeostasis in Tsc2-deficient cells. miR-21 inhibition reduced mitochondrial polarization and function in Tsc2-deficient cells, with and without co-treatment with rapamycin. Importantly, miR-21 inhibition limited Tsc2-deficient tumor growth
, reducing tumor size by approximately 3-fold (
<0.0001). When combined with rapamcyin, miR-21 inhibition showed even more striking efficacy, both during treatment and after treatment cessation, with a 4-fold increase in median survival following rapamycin cessation (
=0.0008). We conclude that miR-21 promotes mTORC1-driven tumorigenesis
a mechanism that involves the mitochondria, and that miR-21 is a potential therapeutic target for TSC-associated hamartomas and other mTORC1-driven tumors, with the potential for synergistic efficacy when combined with rapalogs.</abstract><cop>United States</cop><pub>Impact Journals LLC</pub><pmid>29029388</pmid><doi>10.18632/oncotarget.19947</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record> |
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| title | Rapamycin-induced miR-21 promotes mitochondrial homeostasis and adaptation in mTORC1 activated cells |
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