KLF5-mediated COX2 upregulation contributes to tumorigenesis driven by PTEN deficiency
Tumor suppressor gene PTEN is frequently mutated in a wide variety of cancers. However, the downstream targets or signal transduction pathways of PTEN remain not fully understood. By analyzing Pten-null mouse embryonic fibroblasts (MEFs) cell lines and their isogenic counterparts, we showed that los...
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Veröffentlicht in: | Cellular signalling 2020-11, Vol.75, p.109767-109767, Article 109767 |
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creator | Zhang, Liang Wu, Yuncui Wu, Jing Zhou, Meng Li, Dapeng Wan, Xiaofeng Jin, Fuquan Wang, Yani Lin, Wei Zha, Xiaojun Liu, Yehai |
description | Tumor suppressor gene PTEN is frequently mutated in a wide variety of cancers. However, the downstream targets or signal transduction pathways of PTEN remain not fully understood. By analyzing Pten-null mouse embryonic fibroblasts (MEFs) cell lines and their isogenic counterparts, we showed that loss of PTEN led to increased cyclooxygenase2 (COX2) expression in an AKT-independent manner. Moreover, we demonstrated that PTEN deficiency promotes the transcription of COX2 via upregulation of the transcription factor Krüppel-like factor 5 (KLF5). Knocked down the expression of COX2 suppressed proliferation, migration and tumoral growth of Pten-null cells. Further experiments revealed that COX2 enhanced Pten-null MEFs growth and migration through upregulation of NADPH oxidase 4 (NOX4). In addition, MK-2206, a specific inhibitor of AKT, in combination with celecoxib, a COX2 inhibitor, strongly inhibited Pten-deficient cell growth. We concluded that KLF5/COX2/NOX4 signaling pathway is critical for cell growth and migration caused by the loss of PTEN, and the combination of MK-2206 and celecoxib may be an effective new approach to treating PTEN deficiency related tumors.
•Loss of PTEN upregulates COX2 in an AKT-independent manner.•PTEN deficiency promotes the expression of COX2 through upregulation of KLF5.•Depletion of COX2 suppresses PTEN deficiency-induced tumorigenesis.•COX2 increases the proliferative and migratory capacities of Pten-null cells via elevation of NOX4 expression.•Celecoxib in combination with MK-2206 plays a stronger inhibitory role on the growth of Pten-/- cells than either drug alone. |
doi_str_mv | 10.1016/j.cellsig.2020.109767 |
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•Loss of PTEN upregulates COX2 in an AKT-independent manner.•PTEN deficiency promotes the expression of COX2 through upregulation of KLF5.•Depletion of COX2 suppresses PTEN deficiency-induced tumorigenesis.•COX2 increases the proliferative and migratory capacities of Pten-null cells via elevation of NOX4 expression.•Celecoxib in combination with MK-2206 plays a stronger inhibitory role on the growth of Pten-/- cells than either drug alone.</description><identifier>ISSN: 0898-6568</identifier><identifier>EISSN: 1873-3913</identifier><identifier>DOI: 10.1016/j.cellsig.2020.109767</identifier><identifier>PMID: 32890667</identifier><language>eng</language><publisher>England: Elsevier Inc</publisher><subject>Celecoxib ; COX2 ; KLF5 ; MK-2206 ; PTEN</subject><ispartof>Cellular signalling, 2020-11, Vol.75, p.109767-109767, Article 109767</ispartof><rights>2020 Elsevier Inc.</rights><rights>Copyright © 2020 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c365t-1ee71c8ae1833cfda6d0292502a625f6913b99b053c0a2c2d828e19b205ed70e3</citedby><cites>FETCH-LOGICAL-c365t-1ee71c8ae1833cfda6d0292502a625f6913b99b053c0a2c2d828e19b205ed70e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.cellsig.2020.109767$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32890667$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zhang, Liang</creatorcontrib><creatorcontrib>Wu, Yuncui</creatorcontrib><creatorcontrib>Wu, Jing</creatorcontrib><creatorcontrib>Zhou, Meng</creatorcontrib><creatorcontrib>Li, Dapeng</creatorcontrib><creatorcontrib>Wan, Xiaofeng</creatorcontrib><creatorcontrib>Jin, Fuquan</creatorcontrib><creatorcontrib>Wang, Yani</creatorcontrib><creatorcontrib>Lin, Wei</creatorcontrib><creatorcontrib>Zha, Xiaojun</creatorcontrib><creatorcontrib>Liu, Yehai</creatorcontrib><title>KLF5-mediated COX2 upregulation contributes to tumorigenesis driven by PTEN deficiency</title><title>Cellular signalling</title><addtitle>Cell Signal</addtitle><description>Tumor suppressor gene PTEN is frequently mutated in a wide variety of cancers. However, the downstream targets or signal transduction pathways of PTEN remain not fully understood. By analyzing Pten-null mouse embryonic fibroblasts (MEFs) cell lines and their isogenic counterparts, we showed that loss of PTEN led to increased cyclooxygenase2 (COX2) expression in an AKT-independent manner. Moreover, we demonstrated that PTEN deficiency promotes the transcription of COX2 via upregulation of the transcription factor Krüppel-like factor 5 (KLF5). Knocked down the expression of COX2 suppressed proliferation, migration and tumoral growth of Pten-null cells. Further experiments revealed that COX2 enhanced Pten-null MEFs growth and migration through upregulation of NADPH oxidase 4 (NOX4). In addition, MK-2206, a specific inhibitor of AKT, in combination with celecoxib, a COX2 inhibitor, strongly inhibited Pten-deficient cell growth. We concluded that KLF5/COX2/NOX4 signaling pathway is critical for cell growth and migration caused by the loss of PTEN, and the combination of MK-2206 and celecoxib may be an effective new approach to treating PTEN deficiency related tumors.
•Loss of PTEN upregulates COX2 in an AKT-independent manner.•PTEN deficiency promotes the expression of COX2 through upregulation of KLF5.•Depletion of COX2 suppresses PTEN deficiency-induced tumorigenesis.•COX2 increases the proliferative and migratory capacities of Pten-null cells via elevation of NOX4 expression.•Celecoxib in combination with MK-2206 plays a stronger inhibitory role on the growth of Pten-/- cells than either drug alone.</description><subject>Celecoxib</subject><subject>COX2</subject><subject>KLF5</subject><subject>MK-2206</subject><subject>PTEN</subject><issn>0898-6568</issn><issn>1873-3913</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><recordid>eNqF0EtLAzEQB_AgitbHR1By9LI1jyabnERKfWBRDyreQjaZLSntbk2yQr-9W1u9ehoY_jPD_BA6p2RICZVX86GDxSKF2ZARtunpUpZ7aEBVyQuuKd9HA6K0KqSQ6ggdpzQnhAoi2SE64kxpImU5QO-P01tRLMEHm8Hj8fMHw90qwqxb2BzaBru2yTFUXYaEc4tzt2xjmEEDKSTsY_iCBldr_PI6ecIe6uACNG59ig5qu0hwtqsn6O128jq-L6bPdw_jm2nhuBS5oAAldcoCVZy72lvpCdNMEGYlE7Xs36i0rojgjljmmFdMAdUVIwJ8SYCfoMvt3lVsPztI2SxD2sDYBtouGTYakZEstaR9VGyjLrYpRajNKoaljWtDidmQmrnZkZoNqdmS9nMXuxNd1Tv9Tf0a9oHrbQD6R78CRJN-EHrTCC4b34Z_TnwD_JOJww</recordid><startdate>202011</startdate><enddate>202011</enddate><creator>Zhang, Liang</creator><creator>Wu, Yuncui</creator><creator>Wu, Jing</creator><creator>Zhou, Meng</creator><creator>Li, Dapeng</creator><creator>Wan, Xiaofeng</creator><creator>Jin, Fuquan</creator><creator>Wang, Yani</creator><creator>Lin, Wei</creator><creator>Zha, Xiaojun</creator><creator>Liu, Yehai</creator><general>Elsevier Inc</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>202011</creationdate><title>KLF5-mediated COX2 upregulation contributes to tumorigenesis driven by PTEN deficiency</title><author>Zhang, Liang ; Wu, Yuncui ; Wu, Jing ; Zhou, Meng ; Li, Dapeng ; Wan, Xiaofeng ; Jin, Fuquan ; Wang, Yani ; Lin, Wei ; Zha, Xiaojun ; Liu, Yehai</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c365t-1ee71c8ae1833cfda6d0292502a625f6913b99b053c0a2c2d828e19b205ed70e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Celecoxib</topic><topic>COX2</topic><topic>KLF5</topic><topic>MK-2206</topic><topic>PTEN</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zhang, Liang</creatorcontrib><creatorcontrib>Wu, Yuncui</creatorcontrib><creatorcontrib>Wu, Jing</creatorcontrib><creatorcontrib>Zhou, Meng</creatorcontrib><creatorcontrib>Li, Dapeng</creatorcontrib><creatorcontrib>Wan, Xiaofeng</creatorcontrib><creatorcontrib>Jin, Fuquan</creatorcontrib><creatorcontrib>Wang, Yani</creatorcontrib><creatorcontrib>Lin, Wei</creatorcontrib><creatorcontrib>Zha, Xiaojun</creatorcontrib><creatorcontrib>Liu, Yehai</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Cellular signalling</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhang, Liang</au><au>Wu, Yuncui</au><au>Wu, Jing</au><au>Zhou, Meng</au><au>Li, Dapeng</au><au>Wan, Xiaofeng</au><au>Jin, Fuquan</au><au>Wang, Yani</au><au>Lin, Wei</au><au>Zha, Xiaojun</au><au>Liu, Yehai</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>KLF5-mediated COX2 upregulation contributes to tumorigenesis driven by PTEN deficiency</atitle><jtitle>Cellular signalling</jtitle><addtitle>Cell Signal</addtitle><date>2020-11</date><risdate>2020</risdate><volume>75</volume><spage>109767</spage><epage>109767</epage><pages>109767-109767</pages><artnum>109767</artnum><issn>0898-6568</issn><eissn>1873-3913</eissn><abstract>Tumor suppressor gene PTEN is frequently mutated in a wide variety of cancers. However, the downstream targets or signal transduction pathways of PTEN remain not fully understood. By analyzing Pten-null mouse embryonic fibroblasts (MEFs) cell lines and their isogenic counterparts, we showed that loss of PTEN led to increased cyclooxygenase2 (COX2) expression in an AKT-independent manner. Moreover, we demonstrated that PTEN deficiency promotes the transcription of COX2 via upregulation of the transcription factor Krüppel-like factor 5 (KLF5). Knocked down the expression of COX2 suppressed proliferation, migration and tumoral growth of Pten-null cells. Further experiments revealed that COX2 enhanced Pten-null MEFs growth and migration through upregulation of NADPH oxidase 4 (NOX4). In addition, MK-2206, a specific inhibitor of AKT, in combination with celecoxib, a COX2 inhibitor, strongly inhibited Pten-deficient cell growth. We concluded that KLF5/COX2/NOX4 signaling pathway is critical for cell growth and migration caused by the loss of PTEN, and the combination of MK-2206 and celecoxib may be an effective new approach to treating PTEN deficiency related tumors.
•Loss of PTEN upregulates COX2 in an AKT-independent manner.•PTEN deficiency promotes the expression of COX2 through upregulation of KLF5.•Depletion of COX2 suppresses PTEN deficiency-induced tumorigenesis.•COX2 increases the proliferative and migratory capacities of Pten-null cells via elevation of NOX4 expression.•Celecoxib in combination with MK-2206 plays a stronger inhibitory role on the growth of Pten-/- cells than either drug alone.</abstract><cop>England</cop><pub>Elsevier Inc</pub><pmid>32890667</pmid><doi>10.1016/j.cellsig.2020.109767</doi><tpages>1</tpages></addata></record> |
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subjects | Celecoxib COX2 KLF5 MK-2206 PTEN |
title | KLF5-mediated COX2 upregulation contributes to tumorigenesis driven by PTEN deficiency |
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