Gamma-synuclein promotes cancer cell survival and inhibits stress- and chemotherapy drug-induced apoptosis by modulating MAPK pathways
Synucleins are a family of highly conserved small proteins predominantly expressed in neurons. Recently we and others have found that gamma-synuclein is dramatically up-regulated in the vast majority of late-stage breast and ovarian cancers and that gamma-synuclein over-expression can enhance tumori...
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Veröffentlicht in: | The Journal of biological chemistry 2002-09, Vol.277 (38), p.35050-35060 |
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creator | Pan, Zhong-Zong Bruening, Wendy Giasson, Benoit I Lee, Virginia M-Y Godwin, Andrew K |
description | Synucleins are a family of highly conserved small proteins predominantly expressed in neurons. Recently we and others have found that gamma-synuclein is dramatically up-regulated in the vast majority of late-stage breast and ovarian cancers and that gamma-synuclein over-expression can enhance tumorigenicity. In the current study, we have found that gamma-synuclein is associated with two major mitogen-activated kinases (MAPKs), i.e. extracellular signal-regulated protein kinases (ERK1/2) and c-Jun N-terminal kinase 1 (JNK1), and have shown that over-expression of gamma-synuclein leads to constitutive activation of ERK1/2 and down-regulation of JNK1 in response to a host of environmental stress signals, including UV, arsenate, and heat shock. We also tested the effects of gamma-synuclein on apoptosis and activation of JNK and ERK in response to several chemotherapy drugs. We have found that gamma-synuclein-expressing cells are significantly more resistant to the chemotherapeutic drugs paclitaxel and vinblastine as compared with the parental cells. The resistance to paclitaxel can be partially obliterated when ERK activity is inhibited using a MEK1/2 inhibitor. Activation of JNK and its downstream caspase-3 by paclitaxel or vinblastine is significantly down-regulated in gamma-synuclein-expressing cells, indicating that the paclitaxel- or vinblastine-activated apoptosis pathway is blocked by gamma-synuclein. In contrast to paclitaxel and vinblastine, etoposide does not activate JNK, and gamma-synuclein over-expression has no apparent effect on this drug-induced apoptosis. Taken together, our data indicate that oncogenic activation of gamma-synuclein contributes to the development of breast and ovarian cancer by promoting tumor cell survival under adverse conditions and by providing resistance to certain chemotherapeutic drugs. |
doi_str_mv | 10.1074/jbc.M201650200 |
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Recently we and others have found that gamma-synuclein is dramatically up-regulated in the vast majority of late-stage breast and ovarian cancers and that gamma-synuclein over-expression can enhance tumorigenicity. In the current study, we have found that gamma-synuclein is associated with two major mitogen-activated kinases (MAPKs), i.e. extracellular signal-regulated protein kinases (ERK1/2) and c-Jun N-terminal kinase 1 (JNK1), and have shown that over-expression of gamma-synuclein leads to constitutive activation of ERK1/2 and down-regulation of JNK1 in response to a host of environmental stress signals, including UV, arsenate, and heat shock. We also tested the effects of gamma-synuclein on apoptosis and activation of JNK and ERK in response to several chemotherapy drugs. We have found that gamma-synuclein-expressing cells are significantly more resistant to the chemotherapeutic drugs paclitaxel and vinblastine as compared with the parental cells. The resistance to paclitaxel can be partially obliterated when ERK activity is inhibited using a MEK1/2 inhibitor. Activation of JNK and its downstream caspase-3 by paclitaxel or vinblastine is significantly down-regulated in gamma-synuclein-expressing cells, indicating that the paclitaxel- or vinblastine-activated apoptosis pathway is blocked by gamma-synuclein. In contrast to paclitaxel and vinblastine, etoposide does not activate JNK, and gamma-synuclein over-expression has no apparent effect on this drug-induced apoptosis. Taken together, our data indicate that oncogenic activation of gamma-synuclein contributes to the development of breast and ovarian cancer by promoting tumor cell survival under adverse conditions and by providing resistance to certain chemotherapeutic drugs.</description><identifier>ISSN: 0021-9258</identifier><identifier>DOI: 10.1074/jbc.M201650200</identifier><identifier>PMID: 12121974</identifier><language>eng</language><publisher>United States</publisher><subject>Antineoplastic Agents - therapeutic use ; Apoptosis - physiology ; Cell Survival - physiology ; Drug Resistance, Neoplasm ; Enzyme Activation ; Female ; gamma-Synuclein ; Humans ; MAP Kinase Signaling System ; Nerve Tissue Proteins - physiology ; Ovarian Neoplasms - drug therapy ; Ovarian Neoplasms - pathology ; Precipitin Tests ; Synucleins ; Tumor Cells, Cultured</subject><ispartof>The Journal of biological chemistry, 2002-09, Vol.277 (38), p.35050-35060</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c331t-a15290c90fc5a0fc1d421f7252e705519c7307e6bdbbc6ab7aa0e6d1af0322bb3</citedby><cites>FETCH-LOGICAL-c331t-a15290c90fc5a0fc1d421f7252e705519c7307e6bdbbc6ab7aa0e6d1af0322bb3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12121974$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Pan, Zhong-Zong</creatorcontrib><creatorcontrib>Bruening, Wendy</creatorcontrib><creatorcontrib>Giasson, Benoit I</creatorcontrib><creatorcontrib>Lee, Virginia M-Y</creatorcontrib><creatorcontrib>Godwin, Andrew K</creatorcontrib><title>Gamma-synuclein promotes cancer cell survival and inhibits stress- and chemotherapy drug-induced apoptosis by modulating MAPK pathways</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>Synucleins are a family of highly conserved small proteins predominantly expressed in neurons. Recently we and others have found that gamma-synuclein is dramatically up-regulated in the vast majority of late-stage breast and ovarian cancers and that gamma-synuclein over-expression can enhance tumorigenicity. In the current study, we have found that gamma-synuclein is associated with two major mitogen-activated kinases (MAPKs), i.e. extracellular signal-regulated protein kinases (ERK1/2) and c-Jun N-terminal kinase 1 (JNK1), and have shown that over-expression of gamma-synuclein leads to constitutive activation of ERK1/2 and down-regulation of JNK1 in response to a host of environmental stress signals, including UV, arsenate, and heat shock. We also tested the effects of gamma-synuclein on apoptosis and activation of JNK and ERK in response to several chemotherapy drugs. We have found that gamma-synuclein-expressing cells are significantly more resistant to the chemotherapeutic drugs paclitaxel and vinblastine as compared with the parental cells. The resistance to paclitaxel can be partially obliterated when ERK activity is inhibited using a MEK1/2 inhibitor. Activation of JNK and its downstream caspase-3 by paclitaxel or vinblastine is significantly down-regulated in gamma-synuclein-expressing cells, indicating that the paclitaxel- or vinblastine-activated apoptosis pathway is blocked by gamma-synuclein. In contrast to paclitaxel and vinblastine, etoposide does not activate JNK, and gamma-synuclein over-expression has no apparent effect on this drug-induced apoptosis. Taken together, our data indicate that oncogenic activation of gamma-synuclein contributes to the development of breast and ovarian cancer by promoting tumor cell survival under adverse conditions and by providing resistance to certain chemotherapeutic drugs.</description><subject>Antineoplastic Agents - therapeutic use</subject><subject>Apoptosis - physiology</subject><subject>Cell Survival - physiology</subject><subject>Drug Resistance, Neoplasm</subject><subject>Enzyme Activation</subject><subject>Female</subject><subject>gamma-Synuclein</subject><subject>Humans</subject><subject>MAP Kinase Signaling System</subject><subject>Nerve Tissue Proteins - physiology</subject><subject>Ovarian Neoplasms - drug therapy</subject><subject>Ovarian Neoplasms - pathology</subject><subject>Precipitin Tests</subject><subject>Synucleins</subject><subject>Tumor Cells, Cultured</subject><issn>0021-9258</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2002</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkElPw0AMhecAomW5ckRz4pbimWzkWFVQEK3gAOfIs6SdKhvjBJQ_wO8mpZWwJVuynp_0PsauBcwEpNHdTunZWoJIYpAAJ2wKIEWQyfh-ws6JdjBWlIkzNhFy7CyNpuxniVWFAQ11r0vrat76pmo6S1xjra3n2pYlp95_uS8sOdaGu3rrlOuIU-ctUfB31Fs7vm2tx3bgxvebwNWm19ZwbJu2a8gRVwOvGtOX2Ll6w9fztxfeYrf9xoEu2WmBJdmr475gH48P74unYPW6fF7MV4EOQ9EFKGKZgc6g0DGOQ5hIiiKVsbQpxLHIdBpCahNllNIJqhQRbGIEFhBKqVR4wW4PvmPMz95Sl1eO9hGxtk1PeSohE5FMRuHsINS-IfK2yFvvKvRDLiDf085H2vk_7fHh5ujcq8qaf_kRdfgL_FGAYA</recordid><startdate>20020920</startdate><enddate>20020920</enddate><creator>Pan, Zhong-Zong</creator><creator>Bruening, Wendy</creator><creator>Giasson, Benoit I</creator><creator>Lee, Virginia M-Y</creator><creator>Godwin, Andrew K</creator><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></search><sort><creationdate>20020920</creationdate><title>Gamma-synuclein promotes cancer cell survival and inhibits stress- and chemotherapy drug-induced apoptosis by modulating MAPK pathways</title><author>Pan, Zhong-Zong ; Bruening, Wendy ; Giasson, Benoit I ; Lee, Virginia M-Y ; Godwin, Andrew K</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c331t-a15290c90fc5a0fc1d421f7252e705519c7307e6bdbbc6ab7aa0e6d1af0322bb3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2002</creationdate><topic>Antineoplastic Agents - therapeutic use</topic><topic>Apoptosis - physiology</topic><topic>Cell Survival - physiology</topic><topic>Drug Resistance, Neoplasm</topic><topic>Enzyme Activation</topic><topic>Female</topic><topic>gamma-Synuclein</topic><topic>Humans</topic><topic>MAP Kinase Signaling System</topic><topic>Nerve Tissue Proteins - physiology</topic><topic>Ovarian Neoplasms - drug therapy</topic><topic>Ovarian Neoplasms - pathology</topic><topic>Precipitin Tests</topic><topic>Synucleins</topic><topic>Tumor Cells, Cultured</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Pan, Zhong-Zong</creatorcontrib><creatorcontrib>Bruening, Wendy</creatorcontrib><creatorcontrib>Giasson, Benoit I</creatorcontrib><creatorcontrib>Lee, Virginia M-Y</creatorcontrib><creatorcontrib>Godwin, Andrew K</creatorcontrib><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><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Pan, Zhong-Zong</au><au>Bruening, Wendy</au><au>Giasson, Benoit I</au><au>Lee, Virginia M-Y</au><au>Godwin, Andrew K</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Gamma-synuclein promotes cancer cell survival and inhibits stress- and chemotherapy drug-induced apoptosis by modulating MAPK pathways</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>2002-09-20</date><risdate>2002</risdate><volume>277</volume><issue>38</issue><spage>35050</spage><epage>35060</epage><pages>35050-35060</pages><issn>0021-9258</issn><abstract>Synucleins are a family of highly conserved small proteins predominantly expressed in neurons. Recently we and others have found that gamma-synuclein is dramatically up-regulated in the vast majority of late-stage breast and ovarian cancers and that gamma-synuclein over-expression can enhance tumorigenicity. In the current study, we have found that gamma-synuclein is associated with two major mitogen-activated kinases (MAPKs), i.e. extracellular signal-regulated protein kinases (ERK1/2) and c-Jun N-terminal kinase 1 (JNK1), and have shown that over-expression of gamma-synuclein leads to constitutive activation of ERK1/2 and down-regulation of JNK1 in response to a host of environmental stress signals, including UV, arsenate, and heat shock. We also tested the effects of gamma-synuclein on apoptosis and activation of JNK and ERK in response to several chemotherapy drugs. We have found that gamma-synuclein-expressing cells are significantly more resistant to the chemotherapeutic drugs paclitaxel and vinblastine as compared with the parental cells. The resistance to paclitaxel can be partially obliterated when ERK activity is inhibited using a MEK1/2 inhibitor. Activation of JNK and its downstream caspase-3 by paclitaxel or vinblastine is significantly down-regulated in gamma-synuclein-expressing cells, indicating that the paclitaxel- or vinblastine-activated apoptosis pathway is blocked by gamma-synuclein. In contrast to paclitaxel and vinblastine, etoposide does not activate JNK, and gamma-synuclein over-expression has no apparent effect on this drug-induced apoptosis. Taken together, our data indicate that oncogenic activation of gamma-synuclein contributes to the development of breast and ovarian cancer by promoting tumor cell survival under adverse conditions and by providing resistance to certain chemotherapeutic drugs.</abstract><cop>United States</cop><pmid>12121974</pmid><doi>10.1074/jbc.M201650200</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Antineoplastic Agents - therapeutic use Apoptosis - physiology Cell Survival - physiology Drug Resistance, Neoplasm Enzyme Activation Female gamma-Synuclein Humans MAP Kinase Signaling System Nerve Tissue Proteins - physiology Ovarian Neoplasms - drug therapy Ovarian Neoplasms - pathology Precipitin Tests Synucleins Tumor Cells, Cultured |
title | Gamma-synuclein promotes cancer cell survival and inhibits stress- and chemotherapy drug-induced apoptosis by modulating MAPK pathways |
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