Suppression of the invasive potential of Glioblastoma cells by mTOR inhibitors involves modulation of NFκB and PKC-α signaling
Glioblastoma (GBM) is the most aggressive type of brain tumors in adults with survival period
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| Veröffentlicht in: | Scientific reports 2016-03, Vol.6 (1), p.22455-22455, Article 22455 |
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| creator | Chandrika, Goparaju Natesh, Kumar Ranade, Deepak Chugh, Ashish Shastry, Padma |
| description | Glioblastoma (GBM) is the most aggressive type of brain tumors in adults with survival period |
| doi_str_mv | 10.1038/srep22455 |
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The role of mTOR pathway is documented in invasion and migration, the features associated with aggressive phenotype in human GBM. However, most of the preclinical and clinical studies with mTOR inhibitors are focused on antiproliferative and cytotoxic activity in GBM. In this study, we demonstrate that mTOR inhibitors-rapamycin (RAP), temisirolimus (TEM), torin-1 (TOR) and PP242 suppress invasion and migration induced by Tumor Necrosis Factor-α (TNFα) and tumor promoter, Phorbol 12-myristate 13-acetate (PMA) and also reduce the expression of the TNFα and IL1β suggesting their potential to regulate factors in microenvironment that support tumor progression. The mTOR inhibitors significantly decreased MMP-2 and MMP-9 mRNA, protein and activity that was enhanced by TNFα and PMA. The effect was mediated through reduction of Protein kinase C alpha (PKC-α) activity and downregulation of NFκB. TNFα- induced transcripts of NFκB targets -VEGF, pentraxin-3, cathepsin-B and paxillin, crucial in invasion were restored to basal level by these inhibitors. With limited therapeutic interventions currently available for GBM, our findings are significant and suggest that mTOR inhibitors may be explored as anti-invasive drugs for GBM treatment.</description><identifier>ISSN: 2045-2322</identifier><identifier>EISSN: 2045-2322</identifier><identifier>DOI: 10.1038/srep22455</identifier><identifier>PMID: 26940200</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/1 ; 13/106 ; 13/95 ; 14 ; 38 ; 38/90 ; 631/67 ; 692/4028/67/1922 ; 82 ; 96 ; Antineoplastic Agents - pharmacology ; Brain Neoplasms - drug therapy ; Brain Neoplasms - pathology ; Cell Line, Tumor ; Cell Movement - drug effects ; Glioblastoma - drug therapy ; Glioblastoma - pathology ; Humanities and Social Sciences ; Humans ; Indoles - pharmacology ; Matrix Metalloproteinase 2 - metabolism ; Matrix Metalloproteinase 9 - metabolism ; multidisciplinary ; Naphthyridines - pharmacology ; Neoplasm Invasiveness - prevention & control ; NF-kappa B - metabolism ; Phenylacetates - pharmacology ; Protein Kinase C-alpha - metabolism ; Purines - pharmacology ; Science ; Signal Transduction - drug effects ; Sirolimus - pharmacology ; TOR Serine-Threonine Kinases - antagonists & inhibitors ; Tumor Microenvironment - drug effects ; Tumor Necrosis Factor-alpha - metabolism ; Vascular Endothelial Growth Factor A - metabolism</subject><ispartof>Scientific reports, 2016-03, Vol.6 (1), p.22455-22455, Article 22455</ispartof><rights>The Author(s) 2016</rights><rights>Copyright © 2016, Macmillan Publishers Limited 2016 Macmillan Publishers Limited</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c410t-a91da7c7c0601991d4afcab894a6b94840340c1d55d02441d51407301afbb6d63</citedby><cites>FETCH-LOGICAL-c410t-a91da7c7c0601991d4afcab894a6b94840340c1d55d02441d51407301afbb6d63</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/PMC4778030/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4778030/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,27924,27925,41120,42189,51576,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26940200$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chandrika, Goparaju</creatorcontrib><creatorcontrib>Natesh, Kumar</creatorcontrib><creatorcontrib>Ranade, Deepak</creatorcontrib><creatorcontrib>Chugh, Ashish</creatorcontrib><creatorcontrib>Shastry, Padma</creatorcontrib><title>Suppression of the invasive potential of Glioblastoma cells by mTOR inhibitors involves modulation of NFκB and PKC-α signaling</title><title>Scientific reports</title><addtitle>Sci Rep</addtitle><addtitle>Sci Rep</addtitle><description>Glioblastoma (GBM) is the most aggressive type of brain tumors in adults with survival period <1.5 years of patients. The role of mTOR pathway is documented in invasion and migration, the features associated with aggressive phenotype in human GBM. However, most of the preclinical and clinical studies with mTOR inhibitors are focused on antiproliferative and cytotoxic activity in GBM. In this study, we demonstrate that mTOR inhibitors-rapamycin (RAP), temisirolimus (TEM), torin-1 (TOR) and PP242 suppress invasion and migration induced by Tumor Necrosis Factor-α (TNFα) and tumor promoter, Phorbol 12-myristate 13-acetate (PMA) and also reduce the expression of the TNFα and IL1β suggesting their potential to regulate factors in microenvironment that support tumor progression. The mTOR inhibitors significantly decreased MMP-2 and MMP-9 mRNA, protein and activity that was enhanced by TNFα and PMA. The effect was mediated through reduction of Protein kinase C alpha (PKC-α) activity and downregulation of NFκB. TNFα- induced transcripts of NFκB targets -VEGF, pentraxin-3, cathepsin-B and paxillin, crucial in invasion were restored to basal level by these inhibitors. With limited therapeutic interventions currently available for GBM, our findings are significant and suggest that mTOR inhibitors may be explored as anti-invasive drugs for GBM treatment.</description><subject>13/1</subject><subject>13/106</subject><subject>13/95</subject><subject>14</subject><subject>38</subject><subject>38/90</subject><subject>631/67</subject><subject>692/4028/67/1922</subject><subject>82</subject><subject>96</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Brain Neoplasms - drug therapy</subject><subject>Brain Neoplasms - pathology</subject><subject>Cell Line, Tumor</subject><subject>Cell Movement - drug effects</subject><subject>Glioblastoma - drug therapy</subject><subject>Glioblastoma - pathology</subject><subject>Humanities and Social Sciences</subject><subject>Humans</subject><subject>Indoles - pharmacology</subject><subject>Matrix Metalloproteinase 2 - metabolism</subject><subject>Matrix Metalloproteinase 9 - metabolism</subject><subject>multidisciplinary</subject><subject>Naphthyridines - pharmacology</subject><subject>Neoplasm Invasiveness - prevention & control</subject><subject>NF-kappa B - metabolism</subject><subject>Phenylacetates - pharmacology</subject><subject>Protein Kinase C-alpha - metabolism</subject><subject>Purines - pharmacology</subject><subject>Science</subject><subject>Signal Transduction - drug effects</subject><subject>Sirolimus - pharmacology</subject><subject>TOR Serine-Threonine Kinases - antagonists & inhibitors</subject><subject>Tumor Microenvironment - drug effects</subject><subject>Tumor Necrosis Factor-alpha - metabolism</subject><subject>Vascular Endothelial Growth Factor A - metabolism</subject><issn>2045-2322</issn><issn>2045-2322</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><recordid>eNptkc1u1DAUhS0EolXpghdAXkKlwLXj_G2QYNQfRNUiKGvrJnFmXDlx8E1G6o5XYtuH6DPh0QyjVsIbX-t899i-h7HXAt4LSMsPFMwopcqyZ-xQgsoSmUr5_FF9wI6JbiGuTFZKVC_ZgcwrBRLgkP3-MY9jMETWD9x3fFoZboc1kl0bPvrJDJNFt1HOnfW1Q5p8j7wxzhGv73h_c_09NqxsbScfaNPr3doQ7307O5x2tldnD_efOQ4t__Z1kTz84WSXAzo7LF-xFx06Mse7_Yj9PDu9WVwkl9fnXxafLpNGCZgSrESLRVM0kIOo4kFh12BdVgrzulKlglRBI9osa0EqFQuhoEhBYFfXeZunR-zj1nec6960TfxYQKfHYHsMd9qj1U-Vwa700q-1KooSUogGb3cGwf-aDU26t7SZAw7Gz6RFUUBZqFJmEX23RZvgKebT7a8RoDeh6X1okX3z-F178l9EETjZAhSlYWmCvvVziMOj_7j9BfQxpEQ</recordid><startdate>20160304</startdate><enddate>20160304</enddate><creator>Chandrika, Goparaju</creator><creator>Natesh, Kumar</creator><creator>Ranade, Deepak</creator><creator>Chugh, Ashish</creator><creator>Shastry, Padma</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>C6C</scope><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>7X8</scope><scope>5PM</scope></search><sort><creationdate>20160304</creationdate><title>Suppression of the invasive potential of Glioblastoma cells by mTOR inhibitors involves modulation of NFκB and PKC-α signaling</title><author>Chandrika, Goparaju ; Natesh, Kumar ; Ranade, Deepak ; Chugh, Ashish ; Shastry, Padma</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c410t-a91da7c7c0601991d4afcab894a6b94840340c1d55d02441d51407301afbb6d63</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>13/1</topic><topic>13/106</topic><topic>13/95</topic><topic>14</topic><topic>38</topic><topic>38/90</topic><topic>631/67</topic><topic>692/4028/67/1922</topic><topic>82</topic><topic>96</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Brain Neoplasms - drug therapy</topic><topic>Brain Neoplasms - pathology</topic><topic>Cell Line, Tumor</topic><topic>Cell Movement - drug effects</topic><topic>Glioblastoma - drug therapy</topic><topic>Glioblastoma - pathology</topic><topic>Humanities and Social Sciences</topic><topic>Humans</topic><topic>Indoles - pharmacology</topic><topic>Matrix Metalloproteinase 2 - metabolism</topic><topic>Matrix Metalloproteinase 9 - metabolism</topic><topic>multidisciplinary</topic><topic>Naphthyridines - pharmacology</topic><topic>Neoplasm Invasiveness - prevention & control</topic><topic>NF-kappa B - metabolism</topic><topic>Phenylacetates - pharmacology</topic><topic>Protein Kinase C-alpha - metabolism</topic><topic>Purines - pharmacology</topic><topic>Science</topic><topic>Signal Transduction - drug effects</topic><topic>Sirolimus - pharmacology</topic><topic>TOR Serine-Threonine Kinases - antagonists & inhibitors</topic><topic>Tumor Microenvironment - drug effects</topic><topic>Tumor Necrosis Factor-alpha - metabolism</topic><topic>Vascular Endothelial Growth Factor A - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chandrika, Goparaju</creatorcontrib><creatorcontrib>Natesh, Kumar</creatorcontrib><creatorcontrib>Ranade, Deepak</creatorcontrib><creatorcontrib>Chugh, Ashish</creatorcontrib><creatorcontrib>Shastry, Padma</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>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>Chandrika, Goparaju</au><au>Natesh, Kumar</au><au>Ranade, Deepak</au><au>Chugh, Ashish</au><au>Shastry, Padma</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Suppression of the invasive potential of Glioblastoma cells by mTOR inhibitors involves modulation of NFκB and PKC-α signaling</atitle><jtitle>Scientific reports</jtitle><stitle>Sci Rep</stitle><addtitle>Sci Rep</addtitle><date>2016-03-04</date><risdate>2016</risdate><volume>6</volume><issue>1</issue><spage>22455</spage><epage>22455</epage><pages>22455-22455</pages><artnum>22455</artnum><issn>2045-2322</issn><eissn>2045-2322</eissn><abstract>Glioblastoma (GBM) is the most aggressive type of brain tumors in adults with survival period <1.5 years of patients. The role of mTOR pathway is documented in invasion and migration, the features associated with aggressive phenotype in human GBM. However, most of the preclinical and clinical studies with mTOR inhibitors are focused on antiproliferative and cytotoxic activity in GBM. In this study, we demonstrate that mTOR inhibitors-rapamycin (RAP), temisirolimus (TEM), torin-1 (TOR) and PP242 suppress invasion and migration induced by Tumor Necrosis Factor-α (TNFα) and tumor promoter, Phorbol 12-myristate 13-acetate (PMA) and also reduce the expression of the TNFα and IL1β suggesting their potential to regulate factors in microenvironment that support tumor progression. The mTOR inhibitors significantly decreased MMP-2 and MMP-9 mRNA, protein and activity that was enhanced by TNFα and PMA. The effect was mediated through reduction of Protein kinase C alpha (PKC-α) activity and downregulation of NFκB. TNFα- induced transcripts of NFκB targets -VEGF, pentraxin-3, cathepsin-B and paxillin, crucial in invasion were restored to basal level by these inhibitors. With limited therapeutic interventions currently available for GBM, our findings are significant and suggest that mTOR inhibitors may be explored as anti-invasive drugs for GBM treatment.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>26940200</pmid><doi>10.1038/srep22455</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | 13/1 13/106 13/95 14 38 38/90 631/67 692/4028/67/1922 82 96 Antineoplastic Agents - pharmacology Brain Neoplasms - drug therapy Brain Neoplasms - pathology Cell Line, Tumor Cell Movement - drug effects Glioblastoma - drug therapy Glioblastoma - pathology Humanities and Social Sciences Humans Indoles - pharmacology Matrix Metalloproteinase 2 - metabolism Matrix Metalloproteinase 9 - metabolism multidisciplinary Naphthyridines - pharmacology Neoplasm Invasiveness - prevention & control NF-kappa B - metabolism Phenylacetates - pharmacology Protein Kinase C-alpha - metabolism Purines - pharmacology Science Signal Transduction - drug effects Sirolimus - pharmacology TOR Serine-Threonine Kinases - antagonists & inhibitors Tumor Microenvironment - drug effects Tumor Necrosis Factor-alpha - metabolism Vascular Endothelial Growth Factor A - metabolism |
| title | Suppression of the invasive potential of Glioblastoma cells by mTOR inhibitors involves modulation of NFκB and PKC-α signaling |
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