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Macrophage inhibitory cytokine-1 activates AKT and ERK-1/2 via the transactivation of ErbB2 in human breast and gastric cancer cells
Macrophage inhibitory cytokine-1 (MIC-1) is a member of the transforming growth factor-β superfamily, which is overexpressed in a variety of human cancers, including breast and gastric cancer. The function of MIC-1 in cancer remains controversial and its signaling pathways remain poorly understood....
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Published in: | Carcinogenesis (New York) 2008-04, Vol.29 (4), p.704-712 |
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description | Macrophage inhibitory cytokine-1 (MIC-1) is a member of the transforming growth factor-β superfamily, which is overexpressed in a variety of human cancers, including breast and gastric cancer. The function of MIC-1 in cancer remains controversial and its signaling pathways remain poorly understood. In this study, we demonstrate that MIC-1 induces the transactivation of ErbB2 in SK-BR-3 breast and SNU-216 gastric cancer cells. MIC-1 induced a significant phosphorylation of Akt and ERK-1/2, and also effected an increase in the levels of tyrosine phosphorylation of ErbB1, ErbB2 and ErbB3 in SK-BR-3 and SNU-216 cells. The treatment of these cells with AG825 and AG1478, inhibitors specific for ErbB2 tyrosine kinase, resulted in the complete abolition of MIC-1-induced Akt and ERK-1/2 phosphorylation. Furthermore, the small-interfering RNA-mediated downregulation of ErbB2 significantly reduced not only the phosphorylation of Akt and ERK-1/2 but also the invasiveness of the cells induced by MIC-1. Our results show that ErbB2 activation performs a crucial function in MIC-1-induced signaling pathways. Further investigations revealed that MIC-1 induced the expression of the hypoxia inducible factor-1α protein and the expression of its target genes, including vascular endothelial growth factor, via the activation of the mammalian target of rapamycin (mTOR) signaling pathway. Stimulation of SK-BR-3 with MIC-1 profoundly induces the phosphorylation of mTOR and its downstream substrates, including p70S6K and 4E-BP1. Collectively, these results show that MIC-1 may participate in the malignant progression of certain human cancer cells that overexpress ErbB2 through the transactivation of ErbB2 tyrosine kinase. |
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The function of MIC-1 in cancer remains controversial and its signaling pathways remain poorly understood. In this study, we demonstrate that MIC-1 induces the transactivation of ErbB2 in SK-BR-3 breast and SNU-216 gastric cancer cells. MIC-1 induced a significant phosphorylation of Akt and ERK-1/2, and also effected an increase in the levels of tyrosine phosphorylation of ErbB1, ErbB2 and ErbB3 in SK-BR-3 and SNU-216 cells. The treatment of these cells with AG825 and AG1478, inhibitors specific for ErbB2 tyrosine kinase, resulted in the complete abolition of MIC-1-induced Akt and ERK-1/2 phosphorylation. Furthermore, the small-interfering RNA-mediated downregulation of ErbB2 significantly reduced not only the phosphorylation of Akt and ERK-1/2 but also the invasiveness of the cells induced by MIC-1. Our results show that ErbB2 activation performs a crucial function in MIC-1-induced signaling pathways. Further investigations revealed that MIC-1 induced the expression of the hypoxia inducible factor-1α protein and the expression of its target genes, including vascular endothelial growth factor, via the activation of the mammalian target of rapamycin (mTOR) signaling pathway. Stimulation of SK-BR-3 with MIC-1 profoundly induces the phosphorylation of mTOR and its downstream substrates, including p70S6K and 4E-BP1. Collectively, these results show that MIC-1 may participate in the malignant progression of certain human cancer cells that overexpress ErbB2 through the transactivation of ErbB2 tyrosine kinase.</description><identifier>ISSN: 0143-3334</identifier><identifier>EISSN: 1460-2180</identifier><identifier>DOI: 10.1093/carcin/bgn031</identifier><identifier>PMID: 18258606</identifier><identifier>CODEN: CRNGDP</identifier><language>eng</language><publisher>Oxford: Oxford University Press</publisher><subject>Biological and medical sciences ; Breast Neoplasms - genetics ; Breast Neoplasms - pathology ; Carcinogenesis, carcinogens and anticarcinogens ; Cell Line, Tumor ; Cytokines - physiology ; DNA Primers ; Female ; Gastroenterology. Liver. Pancreas. Abdomen ; Gene Expression Regulation, Neoplastic ; Growth Differentiation Factor 15 ; Gynecology. Andrology. Obstetrics ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit - genetics ; Mammary gland diseases ; Medical sciences ; Mitogen-Activated Protein Kinase 3 ; Mitogen-Activated Protein Kinase Kinases - genetics ; Neoplasm Invasiveness ; Proto-Oncogene Proteins c-akt - metabolism ; Receptor, ErbB-2 - genetics ; Reverse Transcriptase Polymerase Chain Reaction ; RNA Interference ; Stomach Neoplasms - genetics ; Stomach Neoplasms - pathology ; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus ; Transcriptional Activation ; Tumors</subject><ispartof>Carcinogenesis (New York), 2008-04, Vol.29 (4), p.704-712</ispartof><rights>The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org 2008</rights><rights>2008 INIST-CNRS</rights><rights>The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c588t-e49f23e33a78f3662a528df50d42247f3768ff40a89321d98edfefcd23f6992a3</citedby><cites>FETCH-LOGICAL-c588t-e49f23e33a78f3662a528df50d42247f3768ff40a89321d98edfefcd23f6992a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27923,27924</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=20263593$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18258606$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kim, Kwang-Kyu</creatorcontrib><creatorcontrib>Lee, Jung Joon</creatorcontrib><creatorcontrib>Yang, Young</creatorcontrib><creatorcontrib>You, Kwan-Hee</creatorcontrib><creatorcontrib>Lee, Jeong-Hyung</creatorcontrib><title>Macrophage inhibitory cytokine-1 activates AKT and ERK-1/2 via the transactivation of ErbB2 in human breast and gastric cancer cells</title><title>Carcinogenesis (New York)</title><addtitle>Carcinogenesis</addtitle><description>Macrophage inhibitory cytokine-1 (MIC-1) is a member of the transforming growth factor-β superfamily, which is overexpressed in a variety of human cancers, including breast and gastric cancer. The function of MIC-1 in cancer remains controversial and its signaling pathways remain poorly understood. In this study, we demonstrate that MIC-1 induces the transactivation of ErbB2 in SK-BR-3 breast and SNU-216 gastric cancer cells. MIC-1 induced a significant phosphorylation of Akt and ERK-1/2, and also effected an increase in the levels of tyrosine phosphorylation of ErbB1, ErbB2 and ErbB3 in SK-BR-3 and SNU-216 cells. The treatment of these cells with AG825 and AG1478, inhibitors specific for ErbB2 tyrosine kinase, resulted in the complete abolition of MIC-1-induced Akt and ERK-1/2 phosphorylation. Furthermore, the small-interfering RNA-mediated downregulation of ErbB2 significantly reduced not only the phosphorylation of Akt and ERK-1/2 but also the invasiveness of the cells induced by MIC-1. Our results show that ErbB2 activation performs a crucial function in MIC-1-induced signaling pathways. Further investigations revealed that MIC-1 induced the expression of the hypoxia inducible factor-1α protein and the expression of its target genes, including vascular endothelial growth factor, via the activation of the mammalian target of rapamycin (mTOR) signaling pathway. Stimulation of SK-BR-3 with MIC-1 profoundly induces the phosphorylation of mTOR and its downstream substrates, including p70S6K and 4E-BP1. Collectively, these results show that MIC-1 may participate in the malignant progression of certain human cancer cells that overexpress ErbB2 through the transactivation of ErbB2 tyrosine kinase.</description><subject>Biological and medical sciences</subject><subject>Breast Neoplasms - genetics</subject><subject>Breast Neoplasms - pathology</subject><subject>Carcinogenesis, carcinogens and anticarcinogens</subject><subject>Cell Line, Tumor</subject><subject>Cytokines - physiology</subject><subject>DNA Primers</subject><subject>Female</subject><subject>Gastroenterology. Liver. Pancreas. Abdomen</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Growth Differentiation Factor 15</subject><subject>Gynecology. Andrology. Obstetrics</subject><subject>Humans</subject><subject>Hypoxia-Inducible Factor 1, alpha Subunit - genetics</subject><subject>Mammary gland diseases</subject><subject>Medical sciences</subject><subject>Mitogen-Activated Protein Kinase 3</subject><subject>Mitogen-Activated Protein Kinase Kinases - genetics</subject><subject>Neoplasm Invasiveness</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>Receptor, ErbB-2 - genetics</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>RNA Interference</subject><subject>Stomach Neoplasms - genetics</subject><subject>Stomach Neoplasms - pathology</subject><subject>Stomach. Duodenum. Small intestine. Colon. Rectum. Anus</subject><subject>Transcriptional Activation</subject><subject>Tumors</subject><issn>0143-3334</issn><issn>1460-2180</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><recordid>eNqF0UFv0zAUB3ALgVgZHLkiCwnEJdT2S5z4OKayoQ2hoSJNXKxXx269tU6xk4ne-eC4NBqIA_hiH35-fs9_Qp5z9pYzBVOD0fgwXSwDA_6ATHgpWSF4wx6SCeMlFABQHpEnKd0wxiVU6jE54o2oGsnkhPz4iCZ22xUuLfVh5Re-7-KOml3f3fpgC07R9P4Oe5voycWcYmjp7PNFwaeC3nmk_crSPmJII_NdoJ2js7h4J3JBuho2GOgiWkz9r8vLfIjeUIPB2EiNXa_TU_LI4TrZZ-N-TL68n81Pz4vLT2cfTk8uC1M1TV_YUjkBFgDrxoGUAivRtK5ibSlEWTuoZeNcybBRIHirGts660wrwEmlBMIxeX2ou43dt8GmXm982neAwXZD0oIpyUBBhm_-CXmphBR5yUxf_kVvuiGGPIYWXEFVC7ZHxQHlv04pWqe30W8w7jRneh-jPsSoDzFm_2IsOiw2tv2tx9wyeDUCTAbXLidgfLp3gol90n8M0g3b_7459uhTb7_fY4y3WtZQV_r8-qu-AsnV1fWZnsNP-BHCyg</recordid><startdate>20080401</startdate><enddate>20080401</enddate><creator>Kim, Kwang-Kyu</creator><creator>Lee, Jung Joon</creator><creator>Yang, Young</creator><creator>You, Kwan-Hee</creator><creator>Lee, Jeong-Hyung</creator><general>Oxford University Press</general><general>Oxford Publishing Limited (England)</general><scope>BSCLL</scope><scope>IQODW</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>7T5</scope><scope>7TM</scope><scope>7TO</scope><scope>7U7</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>P64</scope><scope>RC3</scope></search><sort><creationdate>20080401</creationdate><title>Macrophage inhibitory cytokine-1 activates AKT and ERK-1/2 via the transactivation of ErbB2 in human breast and gastric cancer cells</title><author>Kim, Kwang-Kyu ; Lee, Jung Joon ; Yang, Young ; You, Kwan-Hee ; Lee, Jeong-Hyung</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c588t-e49f23e33a78f3662a528df50d42247f3768ff40a89321d98edfefcd23f6992a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Biological and medical sciences</topic><topic>Breast Neoplasms - genetics</topic><topic>Breast Neoplasms - pathology</topic><topic>Carcinogenesis, carcinogens and anticarcinogens</topic><topic>Cell Line, Tumor</topic><topic>Cytokines - physiology</topic><topic>DNA Primers</topic><topic>Female</topic><topic>Gastroenterology. Liver. Pancreas. Abdomen</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Growth Differentiation Factor 15</topic><topic>Gynecology. Andrology. Obstetrics</topic><topic>Humans</topic><topic>Hypoxia-Inducible Factor 1, alpha Subunit - genetics</topic><topic>Mammary gland diseases</topic><topic>Medical sciences</topic><topic>Mitogen-Activated Protein Kinase 3</topic><topic>Mitogen-Activated Protein Kinase Kinases - genetics</topic><topic>Neoplasm Invasiveness</topic><topic>Proto-Oncogene Proteins c-akt - metabolism</topic><topic>Receptor, ErbB-2 - genetics</topic><topic>Reverse Transcriptase Polymerase Chain Reaction</topic><topic>RNA Interference</topic><topic>Stomach Neoplasms - genetics</topic><topic>Stomach Neoplasms - pathology</topic><topic>Stomach. Duodenum. Small intestine. Colon. Rectum. Anus</topic><topic>Transcriptional Activation</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kim, Kwang-Kyu</creatorcontrib><creatorcontrib>Lee, Jung Joon</creatorcontrib><creatorcontrib>Yang, Young</creatorcontrib><creatorcontrib>You, Kwan-Hee</creatorcontrib><creatorcontrib>Lee, Jeong-Hyung</creatorcontrib><collection>Istex</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Immunology Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><jtitle>Carcinogenesis (New York)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kim, Kwang-Kyu</au><au>Lee, Jung Joon</au><au>Yang, Young</au><au>You, Kwan-Hee</au><au>Lee, Jeong-Hyung</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Macrophage inhibitory cytokine-1 activates AKT and ERK-1/2 via the transactivation of ErbB2 in human breast and gastric cancer cells</atitle><jtitle>Carcinogenesis (New York)</jtitle><addtitle>Carcinogenesis</addtitle><date>2008-04-01</date><risdate>2008</risdate><volume>29</volume><issue>4</issue><spage>704</spage><epage>712</epage><pages>704-712</pages><issn>0143-3334</issn><eissn>1460-2180</eissn><coden>CRNGDP</coden><abstract>Macrophage inhibitory cytokine-1 (MIC-1) is a member of the transforming growth factor-β superfamily, which is overexpressed in a variety of human cancers, including breast and gastric cancer. The function of MIC-1 in cancer remains controversial and its signaling pathways remain poorly understood. In this study, we demonstrate that MIC-1 induces the transactivation of ErbB2 in SK-BR-3 breast and SNU-216 gastric cancer cells. MIC-1 induced a significant phosphorylation of Akt and ERK-1/2, and also effected an increase in the levels of tyrosine phosphorylation of ErbB1, ErbB2 and ErbB3 in SK-BR-3 and SNU-216 cells. The treatment of these cells with AG825 and AG1478, inhibitors specific for ErbB2 tyrosine kinase, resulted in the complete abolition of MIC-1-induced Akt and ERK-1/2 phosphorylation. Furthermore, the small-interfering RNA-mediated downregulation of ErbB2 significantly reduced not only the phosphorylation of Akt and ERK-1/2 but also the invasiveness of the cells induced by MIC-1. Our results show that ErbB2 activation performs a crucial function in MIC-1-induced signaling pathways. Further investigations revealed that MIC-1 induced the expression of the hypoxia inducible factor-1α protein and the expression of its target genes, including vascular endothelial growth factor, via the activation of the mammalian target of rapamycin (mTOR) signaling pathway. Stimulation of SK-BR-3 with MIC-1 profoundly induces the phosphorylation of mTOR and its downstream substrates, including p70S6K and 4E-BP1. Collectively, these results show that MIC-1 may participate in the malignant progression of certain human cancer cells that overexpress ErbB2 through the transactivation of ErbB2 tyrosine kinase.</abstract><cop>Oxford</cop><pub>Oxford University Press</pub><pmid>18258606</pmid><doi>10.1093/carcin/bgn031</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Biological and medical sciences Breast Neoplasms - genetics Breast Neoplasms - pathology Carcinogenesis, carcinogens and anticarcinogens Cell Line, Tumor Cytokines - physiology DNA Primers Female Gastroenterology. Liver. Pancreas. Abdomen Gene Expression Regulation, Neoplastic Growth Differentiation Factor 15 Gynecology. Andrology. Obstetrics Humans Hypoxia-Inducible Factor 1, alpha Subunit - genetics Mammary gland diseases Medical sciences Mitogen-Activated Protein Kinase 3 Mitogen-Activated Protein Kinase Kinases - genetics Neoplasm Invasiveness Proto-Oncogene Proteins c-akt - metabolism Receptor, ErbB-2 - genetics Reverse Transcriptase Polymerase Chain Reaction RNA Interference Stomach Neoplasms - genetics Stomach Neoplasms - pathology Stomach. Duodenum. Small intestine. Colon. Rectum. Anus Transcriptional Activation Tumors |
title | Macrophage inhibitory cytokine-1 activates AKT and ERK-1/2 via the transactivation of ErbB2 in human breast and gastric cancer cells |
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