Mycophenolic acid inhibits migration and invasion of gastric cancer cells via multiple molecular pathways
Mycophenolic acid (MPA) is the metabolized product and active element of mycophenolate mofetil (MMF) that has been widely used for the prevention of acute graft rejection. MPA potently inhibits inosine monophosphate dehydrogenase (IMPDH) that is up-regulated in many tumors and MPA is known to inhibi...
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| Veröffentlicht in: | PloS one 2013-11, Vol.8 (11), p.e81702 |
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| creator | Dun, Boying Sharma, Ashok Teng, Yong Liu, Haitao Purohit, Sharad Xu, Heng Zeng, Lingwen She, Jin-Xiong |
| description | Mycophenolic acid (MPA) is the metabolized product and active element of mycophenolate mofetil (MMF) that has been widely used for the prevention of acute graft rejection. MPA potently inhibits inosine monophosphate dehydrogenase (IMPDH) that is up-regulated in many tumors and MPA is known to inhibit cancer cell proliferation as well as fibroblast and endothelial cell migration. In this study, we demonstrated for the first time MPA's antimigratory and anti-invasion abilities of MPA-sensitive AGS (gastric cancer) cells. Genome-wide expression analyses using Illumina whole genome microarrays identified 50 genes with ≥2 fold changes and 15 genes with > 4 fold alterations and multiple molecular pathways implicated in cell migration. Real-time RT-PCR analyses of selected genes also confirmed the expression differences. Furthermore, targeted proteomic analyses identified several proteins altered by MPA treatment. Our results indicate that MPA modulates gastric cancer cell migration through down-regulation of a large number of genes (PRKCA, DOCK1, INF2, HSPA5, LRP8 and PDGFRA) and proteins (PRKCA, AKT, SRC, CD147 and MMP1) with promigratory functions as well as up-regulation of a number of genes with antimigratory functions (ATF3, SMAD3, CITED2 and CEAMCAM1). However, a few genes that may promote migration (CYR61 and NOS3) were up-regulated. Therefore, MPA's overall antimigratory role on cancer cells reflects a balance between promigratory and antimigratory signals influenced by MPA treatment. |
| doi_str_mv | 10.1371/journal.pone.0081702 |
| format | Article |
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MPA potently inhibits inosine monophosphate dehydrogenase (IMPDH) that is up-regulated in many tumors and MPA is known to inhibit cancer cell proliferation as well as fibroblast and endothelial cell migration. In this study, we demonstrated for the first time MPA's antimigratory and anti-invasion abilities of MPA-sensitive AGS (gastric cancer) cells. Genome-wide expression analyses using Illumina whole genome microarrays identified 50 genes with ≥2 fold changes and 15 genes with > 4 fold alterations and multiple molecular pathways implicated in cell migration. Real-time RT-PCR analyses of selected genes also confirmed the expression differences. Furthermore, targeted proteomic analyses identified several proteins altered by MPA treatment. Our results indicate that MPA modulates gastric cancer cell migration through down-regulation of a large number of genes (PRKCA, DOCK1, INF2, HSPA5, LRP8 and PDGFRA) and proteins (PRKCA, AKT, SRC, CD147 and MMP1) with promigratory functions as well as up-regulation of a number of genes with antimigratory functions (ATF3, SMAD3, CITED2 and CEAMCAM1). However, a few genes that may promote migration (CYR61 and NOS3) were up-regulated. Therefore, MPA's overall antimigratory role on cancer cells reflects a balance between promigratory and antimigratory signals influenced by MPA treatment.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0081702</identifier><identifier>PMID: 24260584</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Acids ; Activating transcription factor 3 ; AKT protein ; Antibiotics, Antineoplastic - pharmacology ; Biotechnology ; Cancer ; Cancer cells ; Cancer genetics ; Cancer metastasis ; Cancer research ; CD147 antigen ; Cell adhesion & migration ; Cell growth ; Cell Line, Tumor ; Cell migration ; Cell Movement - drug effects ; Cell proliferation ; CYR61 protein ; Endothelial cells ; Gastric cancer ; Gastric Mucosa - drug effects ; Gastric Mucosa - metabolism ; Gastric Mucosa - pathology ; Gene expression ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic - drug effects ; Genes ; Genetic aspects ; Genome, Human ; Genomes ; Genomics ; Graft rejection ; GRP78 protein ; Humans ; Inosine monophosphate ; Kinases ; Medical research ; Medicine ; Metastasis ; Mycophenolate mofetil ; Mycophenolic acid ; Mycophenolic Acid - pharmacology ; Neoplasm Proteins - agonists ; Neoplasm Proteins - antagonists & inhibitors ; Neoplasm Proteins - genetics ; Neoplasm Proteins - metabolism ; Oligonucleotide Array Sequence Analysis ; Pharmaceutical sciences ; Platelet-derived growth factor ; Polymerase chain reaction ; Proteins ; Signal Transduction ; Smad3 protein ; Stomach cancer ; Tumors</subject><ispartof>PloS one, 2013-11, Vol.8 (11), p.e81702</ispartof><rights>COPYRIGHT 2013 Public Library of Science</rights><rights>2013 Dun et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/3.0/ (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>2013 Dun et al 2013 Dun et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-b00af025cfc551c04e12ddcf673b39157a0dfc01838f3642b3e1cfe8a2cf0b7a3</citedby><cites>FETCH-LOGICAL-c692t-b00af025cfc551c04e12ddcf673b39157a0dfc01838f3642b3e1cfe8a2cf0b7a3</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/PMC3829969/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3829969/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,724,777,781,861,882,2096,2915,23847,27905,27906,53772,53774,79349,79350</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24260584$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Xu, Ying</contributor><creatorcontrib>Dun, Boying</creatorcontrib><creatorcontrib>Sharma, Ashok</creatorcontrib><creatorcontrib>Teng, Yong</creatorcontrib><creatorcontrib>Liu, Haitao</creatorcontrib><creatorcontrib>Purohit, Sharad</creatorcontrib><creatorcontrib>Xu, Heng</creatorcontrib><creatorcontrib>Zeng, Lingwen</creatorcontrib><creatorcontrib>She, Jin-Xiong</creatorcontrib><title>Mycophenolic acid inhibits migration and invasion of gastric cancer cells via multiple molecular pathways</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Mycophenolic acid (MPA) is the metabolized product and active element of mycophenolate mofetil (MMF) that has been widely used for the prevention of acute graft rejection. MPA potently inhibits inosine monophosphate dehydrogenase (IMPDH) that is up-regulated in many tumors and MPA is known to inhibit cancer cell proliferation as well as fibroblast and endothelial cell migration. In this study, we demonstrated for the first time MPA's antimigratory and anti-invasion abilities of MPA-sensitive AGS (gastric cancer) cells. Genome-wide expression analyses using Illumina whole genome microarrays identified 50 genes with ≥2 fold changes and 15 genes with > 4 fold alterations and multiple molecular pathways implicated in cell migration. Real-time RT-PCR analyses of selected genes also confirmed the expression differences. Furthermore, targeted proteomic analyses identified several proteins altered by MPA treatment. Our results indicate that MPA modulates gastric cancer cell migration through down-regulation of a large number of genes (PRKCA, DOCK1, INF2, HSPA5, LRP8 and PDGFRA) and proteins (PRKCA, AKT, SRC, CD147 and MMP1) with promigratory functions as well as up-regulation of a number of genes with antimigratory functions (ATF3, SMAD3, CITED2 and CEAMCAM1). However, a few genes that may promote migration (CYR61 and NOS3) were up-regulated. Therefore, MPA's overall antimigratory role on cancer cells reflects a balance between promigratory and antimigratory signals influenced by MPA treatment.</description><subject>Acids</subject><subject>Activating transcription factor 3</subject><subject>AKT protein</subject><subject>Antibiotics, Antineoplastic - pharmacology</subject><subject>Biotechnology</subject><subject>Cancer</subject><subject>Cancer cells</subject><subject>Cancer genetics</subject><subject>Cancer metastasis</subject><subject>Cancer research</subject><subject>CD147 antigen</subject><subject>Cell adhesion & migration</subject><subject>Cell growth</subject><subject>Cell Line, Tumor</subject><subject>Cell migration</subject><subject>Cell Movement - drug effects</subject><subject>Cell proliferation</subject><subject>CYR61 protein</subject><subject>Endothelial cells</subject><subject>Gastric cancer</subject><subject>Gastric Mucosa - drug effects</subject><subject>Gastric Mucosa - metabolism</subject><subject>Gastric Mucosa - pathology</subject><subject>Gene expression</subject><subject>Gene Expression Profiling</subject><subject>Gene Expression Regulation, Neoplastic - drug effects</subject><subject>Genes</subject><subject>Genetic aspects</subject><subject>Genome, Human</subject><subject>Genomes</subject><subject>Genomics</subject><subject>Graft rejection</subject><subject>GRP78 protein</subject><subject>Humans</subject><subject>Inosine monophosphate</subject><subject>Kinases</subject><subject>Medical research</subject><subject>Medicine</subject><subject>Metastasis</subject><subject>Mycophenolate mofetil</subject><subject>Mycophenolic acid</subject><subject>Mycophenolic Acid - pharmacology</subject><subject>Neoplasm Proteins - agonists</subject><subject>Neoplasm Proteins - antagonists & inhibitors</subject><subject>Neoplasm Proteins - genetics</subject><subject>Neoplasm Proteins - metabolism</subject><subject>Oligonucleotide Array Sequence Analysis</subject><subject>Pharmaceutical sciences</subject><subject>Platelet-derived growth factor</subject><subject>Polymerase chain reaction</subject><subject>Proteins</subject><subject>Signal Transduction</subject><subject>Smad3 protein</subject><subject>Stomach cancer</subject><subject>Tumors</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</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>eNqNkl2L1DAUhoso7rr6D0QLguDFjPlo0_ZGWBY_BlYW_LoNp2nSZkibbpKOzr8343SXKShILpKcPO-bw-FNkucYrTEt8NutndwAZj3aQa4RKnGByIPkHFeUrBhB9OHJ-Sx54v0WoZyWjD1OzkhGGMrL7DzRn_fCjp0crNEiBaGbVA-drnXwaa9bB0HbIYXhUN6BP1ysSlvwwUVewCCkS4U0xqc7DWk_maBHI9PeGikmAy4dIXQ_Ye-fJo8UGC-fzftF8v3D-29Xn1bXNx83V5fXK8EqElY1QqAQyYUSeY4FyiQmTSMUK2hNK5wXgBolEC5pqSjLSE0lFkqWQIRCdQH0Inl59B2N9Xyekuc4Y3mV5ZjgSGyORGNhy0ene3B7bkHzPwXrWg4uaGEkzyrIC4xJRSuWFVABqkleQp5VBKRETfR6N_821b1shByCA7MwXb4MuuOt3XFakqpiVTR4NRs4eztJH_7R8ky1ELvSg7LRTPTaC36ZFSVhhOUsUuu_UHE1stci5kTpWF8I3iwEkQnyV2hh8p5vvn75f_bmx5J9fcJ2EkzovDXTIUx-CWZHUDjrvZPqfnIY8UPM76bBDzHnc8yj7MXp1O9Fd7mmvwGXnfls</recordid><startdate>20131115</startdate><enddate>20131115</enddate><creator>Dun, Boying</creator><creator>Sharma, Ashok</creator><creator>Teng, Yong</creator><creator>Liu, Haitao</creator><creator>Purohit, Sharad</creator><creator>Xu, Heng</creator><creator>Zeng, Lingwen</creator><creator>She, Jin-Xiong</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>20131115</creationdate><title>Mycophenolic acid inhibits migration and invasion of gastric cancer cells via multiple molecular pathways</title><author>Dun, Boying ; Sharma, Ashok ; Teng, Yong ; Liu, Haitao ; Purohit, Sharad ; Xu, Heng ; Zeng, Lingwen ; She, Jin-Xiong</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-b00af025cfc551c04e12ddcf673b39157a0dfc01838f3642b3e1cfe8a2cf0b7a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Acids</topic><topic>Activating transcription factor 3</topic><topic>AKT protein</topic><topic>Antibiotics, Antineoplastic - pharmacology</topic><topic>Biotechnology</topic><topic>Cancer</topic><topic>Cancer cells</topic><topic>Cancer genetics</topic><topic>Cancer metastasis</topic><topic>Cancer research</topic><topic>CD147 antigen</topic><topic>Cell adhesion & migration</topic><topic>Cell growth</topic><topic>Cell Line, Tumor</topic><topic>Cell migration</topic><topic>Cell Movement - drug effects</topic><topic>Cell proliferation</topic><topic>CYR61 protein</topic><topic>Endothelial cells</topic><topic>Gastric cancer</topic><topic>Gastric Mucosa - drug effects</topic><topic>Gastric Mucosa - metabolism</topic><topic>Gastric Mucosa - pathology</topic><topic>Gene expression</topic><topic>Gene Expression Profiling</topic><topic>Gene Expression Regulation, Neoplastic - drug effects</topic><topic>Genes</topic><topic>Genetic aspects</topic><topic>Genome, Human</topic><topic>Genomes</topic><topic>Genomics</topic><topic>Graft rejection</topic><topic>GRP78 protein</topic><topic>Humans</topic><topic>Inosine monophosphate</topic><topic>Kinases</topic><topic>Medical research</topic><topic>Medicine</topic><topic>Metastasis</topic><topic>Mycophenolate mofetil</topic><topic>Mycophenolic acid</topic><topic>Mycophenolic Acid - 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MPA potently inhibits inosine monophosphate dehydrogenase (IMPDH) that is up-regulated in many tumors and MPA is known to inhibit cancer cell proliferation as well as fibroblast and endothelial cell migration. In this study, we demonstrated for the first time MPA's antimigratory and anti-invasion abilities of MPA-sensitive AGS (gastric cancer) cells. Genome-wide expression analyses using Illumina whole genome microarrays identified 50 genes with ≥2 fold changes and 15 genes with > 4 fold alterations and multiple molecular pathways implicated in cell migration. Real-time RT-PCR analyses of selected genes also confirmed the expression differences. Furthermore, targeted proteomic analyses identified several proteins altered by MPA treatment. Our results indicate that MPA modulates gastric cancer cell migration through down-regulation of a large number of genes (PRKCA, DOCK1, INF2, HSPA5, LRP8 and PDGFRA) and proteins (PRKCA, AKT, SRC, CD147 and MMP1) with promigratory functions as well as up-regulation of a number of genes with antimigratory functions (ATF3, SMAD3, CITED2 and CEAMCAM1). However, a few genes that may promote migration (CYR61 and NOS3) were up-regulated. Therefore, MPA's overall antimigratory role on cancer cells reflects a balance between promigratory and antimigratory signals influenced by MPA treatment.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>24260584</pmid><doi>10.1371/journal.pone.0081702</doi><tpages>e81702</tpages><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2013-11, Vol.8 (11), p.e81702 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1465945121 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS); EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Acids Activating transcription factor 3 AKT protein Antibiotics, Antineoplastic - pharmacology Biotechnology Cancer Cancer cells Cancer genetics Cancer metastasis Cancer research CD147 antigen Cell adhesion & migration Cell growth Cell Line, Tumor Cell migration Cell Movement - drug effects Cell proliferation CYR61 protein Endothelial cells Gastric cancer Gastric Mucosa - drug effects Gastric Mucosa - metabolism Gastric Mucosa - pathology Gene expression Gene Expression Profiling Gene Expression Regulation, Neoplastic - drug effects Genes Genetic aspects Genome, Human Genomes Genomics Graft rejection GRP78 protein Humans Inosine monophosphate Kinases Medical research Medicine Metastasis Mycophenolate mofetil Mycophenolic acid Mycophenolic Acid - pharmacology Neoplasm Proteins - agonists Neoplasm Proteins - antagonists & inhibitors Neoplasm Proteins - genetics Neoplasm Proteins - metabolism Oligonucleotide Array Sequence Analysis Pharmaceutical sciences Platelet-derived growth factor Polymerase chain reaction Proteins Signal Transduction Smad3 protein Stomach cancer Tumors |
| title | Mycophenolic acid inhibits migration and invasion of gastric cancer cells via multiple molecular pathways |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-20T06%3A37%3A25IST&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=Mycophenolic%20acid%20inhibits%20migration%20and%20invasion%20of%20gastric%20cancer%20cells%20via%20multiple%20molecular%20pathways&rft.jtitle=PloS%20one&rft.au=Dun,%20Boying&rft.date=2013-11-15&rft.volume=8&rft.issue=11&rft.spage=e81702&rft.pages=e81702-&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0081702&rft_dat=%3Cgale_plos_%3EA478262656%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=1465945121&rft_id=info:pmid/24260584&rft_galeid=A478262656&rft_doaj_id=oai_doaj_org_article_49a57112939647a9a0b258a5492aee0d&rfr_iscdi=true |