Ligation of cell surface GRP78 with antibody directed against the COOH-terminal domain of GRP78 suppresses Ras/MAPK and PI 3-kinase/AKT signaling while promoting caspase activation in human prostate cancer cells
We have previously shown that treatment of prostate cancer and melanoma cells expressing GRP78 2 on their cell surface with antibody directed against the COOH-terminal domain of GRP78 up-regulates and activates p53 causing decreased cell proliferation and up-regulated apoptosis. In this report, we...
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| creator | Misra, Uma K. Pizzo, Salvatore V. |
| description | We have previously shown that treatment of prostate cancer and melanoma cells expressing GRP78
2
on their cell surface with antibody directed against the COOH-terminal domain of GRP78 up-regulates and activates p53 causing decreased cell proliferation and up-regulated apoptosis. In this report, we demonstrate that treatment of 1-LN prostate cancer cells with this antibody decreases cell surface expression of GRP78, Akt
Thr308
and Akt
Ser473
kinase activities and reduces phosphorylation of FOXO, and GSK3β. This treatment also suppresses activation of ERK1/2, p38 MAPK, and MKK3/6; however, it up-regulates MKK4 activity. JNK, as determined by its phosphorylation state, is subsequently activated, triggering apoptosis. Incubation of cells with antibody reduced levels of anti-apoptotic Bcl-2, while elevating pro-apoptotic BAD, BAX, and BAK expression as well as cleaved caspases-3, -7, -8, and -9. Silencing GRP78 or p53 gene expression by RNAi prior to antibody treatment abrogated these effects. We conclude that antibody directed against the COOH-terminal domain of GRP78 may prove useful as a pan suppressor of proliferative/survival signaling in cancer cells expressing GRP78 on their cell surface. |
| doi_str_mv | 10.4161/cbt.9.2.10422 |
| format | Article |
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2
on their cell surface with antibody directed against the COOH-terminal domain of GRP78 up-regulates and activates p53 causing decreased cell proliferation and up-regulated apoptosis. In this report, we demonstrate that treatment of 1-LN prostate cancer cells with this antibody decreases cell surface expression of GRP78, Akt
Thr308
and Akt
Ser473
kinase activities and reduces phosphorylation of FOXO, and GSK3β. This treatment also suppresses activation of ERK1/2, p38 MAPK, and MKK3/6; however, it up-regulates MKK4 activity. JNK, as determined by its phosphorylation state, is subsequently activated, triggering apoptosis. Incubation of cells with antibody reduced levels of anti-apoptotic Bcl-2, while elevating pro-apoptotic BAD, BAX, and BAK expression as well as cleaved caspases-3, -7, -8, and -9. Silencing GRP78 or p53 gene expression by RNAi prior to antibody treatment abrogated these effects. We conclude that antibody directed against the COOH-terminal domain of GRP78 may prove useful as a pan suppressor of proliferative/survival signaling in cancer cells expressing GRP78 on their cell surface.</description><identifier>ISSN: 1538-4047</identifier><identifier>EISSN: 1555-8576</identifier><identifier>DOI: 10.4161/cbt.9.2.10422</identifier><identifier>PMID: 20368692</identifier><language>eng</language><publisher>United States: Taylor & Francis</publisher><subject>Adenocarcinoma - metabolism ; Adenocarcinoma - pathology ; Amino Acid Sequence ; Antibodies, Monoclonal - immunology ; Antibodies, Monoclonal - pharmacology ; Antigens, Neoplasm - immunology ; Antigens, Surface - immunology ; Binding ; Biology ; Bioscience ; Calcium ; Cancer ; Caspases - metabolism ; Cell ; Cell Line, Tumor - drug effects ; Cell Line, Tumor - metabolism ; Cycle ; Enzyme Activation - drug effects ; Gene Knockdown Techniques ; Heat-Shock Proteins - antagonists & inhibitors ; Heat-Shock Proteins - chemistry ; Heat-Shock Proteins - immunology ; Heat-Shock Proteins - physiology ; Humans ; Landes ; Male ; MAP Kinase Signaling System - drug effects ; Mitogen-Activated Protein Kinases - physiology ; Molecular Sequence Data ; Neoplasm Proteins - antagonists & inhibitors ; Neoplasm Proteins - chemistry ; Neoplasm Proteins - immunology ; Neoplasm Proteins - physiology ; Organogenesis ; Phosphatidylinositol 3-Kinases - physiology ; Prostatic Neoplasms - metabolism ; Prostatic Neoplasms - pathology ; Protein Kinases - physiology ; Protein Structure, Tertiary ; Proteins ; Proto-Oncogene Proteins c-akt - physiology ; Signal Transduction - drug effects ; Signal Transduction - physiology ; Transcription, Genetic - drug effects</subject><ispartof>Cancer biology & therapy, 2010-01, Vol.9 (2), p.142-152</ispartof><rights>Copyright © 2010 Landes Bioscience 2010</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c589t-d7f9d0dd06b5e3376ebd98df1bc966b57d7b3a663c3eec0ad6d24c8dcc118ad53</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20368692$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Misra, Uma K.</creatorcontrib><creatorcontrib>Pizzo, Salvatore V.</creatorcontrib><title>Ligation of cell surface GRP78 with antibody directed against the COOH-terminal domain of GRP78 suppresses Ras/MAPK and PI 3-kinase/AKT signaling while promoting caspase activation in human prostate cancer cells</title><title>Cancer biology & therapy</title><addtitle>Cancer Biol Ther</addtitle><description>We have previously shown that treatment of prostate cancer and melanoma cells expressing GRP78
2
on their cell surface with antibody directed against the COOH-terminal domain of GRP78 up-regulates and activates p53 causing decreased cell proliferation and up-regulated apoptosis. In this report, we demonstrate that treatment of 1-LN prostate cancer cells with this antibody decreases cell surface expression of GRP78, Akt
Thr308
and Akt
Ser473
kinase activities and reduces phosphorylation of FOXO, and GSK3β. This treatment also suppresses activation of ERK1/2, p38 MAPK, and MKK3/6; however, it up-regulates MKK4 activity. JNK, as determined by its phosphorylation state, is subsequently activated, triggering apoptosis. Incubation of cells with antibody reduced levels of anti-apoptotic Bcl-2, while elevating pro-apoptotic BAD, BAX, and BAK expression as well as cleaved caspases-3, -7, -8, and -9. Silencing GRP78 or p53 gene expression by RNAi prior to antibody treatment abrogated these effects. We conclude that antibody directed against the COOH-terminal domain of GRP78 may prove useful as a pan suppressor of proliferative/survival signaling in cancer cells expressing GRP78 on their cell surface.</description><subject>Adenocarcinoma - metabolism</subject><subject>Adenocarcinoma - pathology</subject><subject>Amino Acid Sequence</subject><subject>Antibodies, Monoclonal - immunology</subject><subject>Antibodies, Monoclonal - pharmacology</subject><subject>Antigens, Neoplasm - immunology</subject><subject>Antigens, Surface - immunology</subject><subject>Binding</subject><subject>Biology</subject><subject>Bioscience</subject><subject>Calcium</subject><subject>Cancer</subject><subject>Caspases - metabolism</subject><subject>Cell</subject><subject>Cell Line, Tumor - drug effects</subject><subject>Cell Line, Tumor - metabolism</subject><subject>Cycle</subject><subject>Enzyme Activation - drug effects</subject><subject>Gene Knockdown Techniques</subject><subject>Heat-Shock Proteins - antagonists & inhibitors</subject><subject>Heat-Shock Proteins - chemistry</subject><subject>Heat-Shock Proteins - immunology</subject><subject>Heat-Shock Proteins - physiology</subject><subject>Humans</subject><subject>Landes</subject><subject>Male</subject><subject>MAP Kinase Signaling System - drug effects</subject><subject>Mitogen-Activated Protein Kinases - physiology</subject><subject>Molecular Sequence Data</subject><subject>Neoplasm Proteins - antagonists & inhibitors</subject><subject>Neoplasm Proteins - chemistry</subject><subject>Neoplasm Proteins - immunology</subject><subject>Neoplasm Proteins - physiology</subject><subject>Organogenesis</subject><subject>Phosphatidylinositol 3-Kinases - physiology</subject><subject>Prostatic Neoplasms - metabolism</subject><subject>Prostatic Neoplasms - pathology</subject><subject>Protein Kinases - physiology</subject><subject>Protein Structure, Tertiary</subject><subject>Proteins</subject><subject>Proto-Oncogene Proteins c-akt - physiology</subject><subject>Signal Transduction - drug effects</subject><subject>Signal Transduction - physiology</subject><subject>Transcription, Genetic - drug effects</subject><issn>1538-4047</issn><issn>1555-8576</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqVkU-P0zAQxSMEYpeFI1fkG6e0dtw4yQVpqWB3tV21WpVz5NiT1ksSB49D1c_JF8Jplp44wMn_fu_NeF4UvWd0tmCCzVXlZ8UsmTG6SJIX0SVL0zTO00y8HPc8jxd0kV1EbxCfKE2yRBSvo4uEcpGLIrmMfq3MTnpjO2JroqBpCA6ulgrIzeMmy8nB-D2RnTeV1UeijQPlQRO5k6ZDT_weyHK9vo09uNZ0siHatuFpdJsMcOh7B4iA5FHi_OF6cx_8NNncER5_DxKE-fX9lqDZBbnpduSwNw2Q3tnW-vGsJPaBIlJ583PqNRTYD63sRgq99BCgToE7_QDfRq9q2SC8e16vom9fv2yXt_FqfXO3vF7FKs0LH-usLjTVmooqBc4zAZUucl2zShUi3GU6q7gUgisOoKjUQicLlWulGMulTvlV9HHyDV38GAB92RocO5Ad2AHLjPM8p7QYyXgiVegXHdRl70wr3bFktBxjLEOMZVEm5SnGwH94dh6qFvSZ_pNbAD5NQKilAStjURkIIzijo-GTHVwYKp4O0nmjGjhXYP9g8L8aRh8MOrn8vB3_0us6aPJJY7raulYerGt06eWxsa52ITSDJf_7EH4DMMzrgg</recordid><startdate>20100101</startdate><enddate>20100101</enddate><creator>Misra, Uma K.</creator><creator>Pizzo, Salvatore V.</creator><general>Taylor & Francis</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>7X8</scope></search><sort><creationdate>20100101</creationdate><title>Ligation of cell surface GRP78 with antibody directed against the COOH-terminal domain of GRP78 suppresses Ras/MAPK and PI 3-kinase/AKT signaling while promoting caspase activation in human prostate cancer cells</title><author>Misra, Uma K. ; Pizzo, Salvatore V.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c589t-d7f9d0dd06b5e3376ebd98df1bc966b57d7b3a663c3eec0ad6d24c8dcc118ad53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Adenocarcinoma - metabolism</topic><topic>Adenocarcinoma - pathology</topic><topic>Amino Acid Sequence</topic><topic>Antibodies, Monoclonal - immunology</topic><topic>Antibodies, Monoclonal - pharmacology</topic><topic>Antigens, Neoplasm - immunology</topic><topic>Antigens, Surface - immunology</topic><topic>Binding</topic><topic>Biology</topic><topic>Bioscience</topic><topic>Calcium</topic><topic>Cancer</topic><topic>Caspases - metabolism</topic><topic>Cell</topic><topic>Cell Line, Tumor - drug effects</topic><topic>Cell Line, Tumor - metabolism</topic><topic>Cycle</topic><topic>Enzyme Activation - drug effects</topic><topic>Gene Knockdown Techniques</topic><topic>Heat-Shock Proteins - antagonists & inhibitors</topic><topic>Heat-Shock Proteins - chemistry</topic><topic>Heat-Shock Proteins - immunology</topic><topic>Heat-Shock Proteins - physiology</topic><topic>Humans</topic><topic>Landes</topic><topic>Male</topic><topic>MAP Kinase Signaling System - drug effects</topic><topic>Mitogen-Activated Protein Kinases - physiology</topic><topic>Molecular Sequence Data</topic><topic>Neoplasm Proteins - antagonists & inhibitors</topic><topic>Neoplasm Proteins - chemistry</topic><topic>Neoplasm Proteins - immunology</topic><topic>Neoplasm Proteins - physiology</topic><topic>Organogenesis</topic><topic>Phosphatidylinositol 3-Kinases - physiology</topic><topic>Prostatic Neoplasms - metabolism</topic><topic>Prostatic Neoplasms - pathology</topic><topic>Protein Kinases - physiology</topic><topic>Protein Structure, Tertiary</topic><topic>Proteins</topic><topic>Proto-Oncogene Proteins c-akt - physiology</topic><topic>Signal Transduction - drug effects</topic><topic>Signal Transduction - physiology</topic><topic>Transcription, Genetic - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Misra, Uma K.</creatorcontrib><creatorcontrib>Pizzo, Salvatore V.</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>Cancer biology & therapy</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Misra, Uma K.</au><au>Pizzo, Salvatore V.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Ligation of cell surface GRP78 with antibody directed against the COOH-terminal domain of GRP78 suppresses Ras/MAPK and PI 3-kinase/AKT signaling while promoting caspase activation in human prostate cancer cells</atitle><jtitle>Cancer biology & therapy</jtitle><addtitle>Cancer Biol Ther</addtitle><date>2010-01-01</date><risdate>2010</risdate><volume>9</volume><issue>2</issue><spage>142</spage><epage>152</epage><pages>142-152</pages><issn>1538-4047</issn><eissn>1555-8576</eissn><abstract>We have previously shown that treatment of prostate cancer and melanoma cells expressing GRP78
2
on their cell surface with antibody directed against the COOH-terminal domain of GRP78 up-regulates and activates p53 causing decreased cell proliferation and up-regulated apoptosis. In this report, we demonstrate that treatment of 1-LN prostate cancer cells with this antibody decreases cell surface expression of GRP78, Akt
Thr308
and Akt
Ser473
kinase activities and reduces phosphorylation of FOXO, and GSK3β. This treatment also suppresses activation of ERK1/2, p38 MAPK, and MKK3/6; however, it up-regulates MKK4 activity. JNK, as determined by its phosphorylation state, is subsequently activated, triggering apoptosis. Incubation of cells with antibody reduced levels of anti-apoptotic Bcl-2, while elevating pro-apoptotic BAD, BAX, and BAK expression as well as cleaved caspases-3, -7, -8, and -9. Silencing GRP78 or p53 gene expression by RNAi prior to antibody treatment abrogated these effects. We conclude that antibody directed against the COOH-terminal domain of GRP78 may prove useful as a pan suppressor of proliferative/survival signaling in cancer cells expressing GRP78 on their cell surface.</abstract><cop>United States</cop><pub>Taylor & Francis</pub><pmid>20368692</pmid><doi>10.4161/cbt.9.2.10422</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 1538-4047 |
| ispartof | Cancer biology & therapy, 2010-01, Vol.9 (2), p.142-152 |
| issn | 1538-4047 1555-8576 |
| language | eng |
| recordid | cdi_pubmed_primary_20368692 |
| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Alma/SFX Local Collection |
| subjects | Adenocarcinoma - metabolism Adenocarcinoma - pathology Amino Acid Sequence Antibodies, Monoclonal - immunology Antibodies, Monoclonal - pharmacology Antigens, Neoplasm - immunology Antigens, Surface - immunology Binding Biology Bioscience Calcium Cancer Caspases - metabolism Cell Cell Line, Tumor - drug effects Cell Line, Tumor - metabolism Cycle Enzyme Activation - drug effects Gene Knockdown Techniques Heat-Shock Proteins - antagonists & inhibitors Heat-Shock Proteins - chemistry Heat-Shock Proteins - immunology Heat-Shock Proteins - physiology Humans Landes Male MAP Kinase Signaling System - drug effects Mitogen-Activated Protein Kinases - physiology Molecular Sequence Data Neoplasm Proteins - antagonists & inhibitors Neoplasm Proteins - chemistry Neoplasm Proteins - immunology Neoplasm Proteins - physiology Organogenesis Phosphatidylinositol 3-Kinases - physiology Prostatic Neoplasms - metabolism Prostatic Neoplasms - pathology Protein Kinases - physiology Protein Structure, Tertiary Proteins Proto-Oncogene Proteins c-akt - physiology Signal Transduction - drug effects Signal Transduction - physiology Transcription, Genetic - drug effects |
| title | Ligation of cell surface GRP78 with antibody directed against the COOH-terminal domain of GRP78 suppresses Ras/MAPK and PI 3-kinase/AKT signaling while promoting caspase activation in human prostate cancer cells |
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