Restoration of compact Golgi morphology in advanced prostate cancer enhances susceptibility to galectin-1-induced apoptosis by modifying mucin O-glycan synthesis
Prostate cancer progression is associated with upregulation of sialyl-T antigen produced by β-galactoside α-2,3-sialyltransferase-1 (ST3Gal1) but not with core 2-associated polylactosamine despite expression of core 2 N-acetylglucosaminyltransferase-L (C2GnT-L/GCNT1). This property allows androgen-r...
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description | Prostate cancer progression is associated with upregulation of sialyl-T antigen produced by β-galactoside α-2,3-sialyltransferase-1 (ST3Gal1) but not with core 2-associated polylactosamine despite expression of core 2 N-acetylglucosaminyltransferase-L (C2GnT-L/GCNT1). This property allows androgen-refractory prostate cancer cells to evade galectin-1 (LGALS1)-induced apoptosis, but the mechanism is not known. We have recently reported that Golgi targeting of glycosyltransferases is mediated by golgins: giantin (GOLGB1) for C2GnT-M (GCNT3) and GM130 (GOLGA2)-GRASP65 (GORASP1) or GM130-giantin for core 1 synthase. Here, we show that for Golgi targeting, C2GnT-L also uses giantin exclusively whereas ST3Gal1 uses either giantin or GM130-GRASP65. In addition, the compact Golgi morphology is detected in both androgen-sensitive prostate cancer and normal prostate cells, but fragmented Golgi and mislocalization of C2GnT-L are found in androgen-refractory cells as well as primary prostate tumors (Gleason grade 2-4). Furthermore, failure of giantin monomers to be phosphorylated and dimerized prevents Golgi from forming compact morphology and C2GnT-L from targeting the Golgi. On the other hand, ST3Gal1 reaches the Golgi by an alternate site, GM130-GRASP65. Interestingly, inhibition or knockdown of non-muscle myosin IIA (MYH9) motor protein frees up Rab6a GTPase to promote phosphorylation of giantin by polo-like kinase 3 (PLK3), which is followed by dimerization of giantin assisted by protein disulfide isomerase A3 (PDIA3), and restoration of compact Golgi morphology and targeting of C2GnT-L. Finally, the Golgi relocation of C2GnT-L in androgen-refractory cells results in their increased susceptibility to galectin-1-induced apoptosis by replacing sialyl-T antigen with polylactosamine.
This study demonstrates the importance of Golgi morphology and regulation of glycosylation and provides insight into how the Golgi influences cancer progression and metastasis. |
doi_str_mv | 10.1158/1541-7786.MCR-14-0291-T |
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This study demonstrates the importance of Golgi morphology and regulation of glycosylation and provides insight into how the Golgi influences cancer progression and metastasis.</description><identifier>ISSN: 1541-7786</identifier><identifier>EISSN: 1557-3125</identifier><identifier>DOI: 10.1158/1541-7786.MCR-14-0291-T</identifier><identifier>PMID: 25086069</identifier><language>eng</language><publisher>United States</publisher><subject>Apoptosis ; Autoantigens - metabolism ; Cell Line, Tumor ; Dimerization ; Galectin 1 - metabolism ; Glycosylation ; Golgi Apparatus - metabolism ; Humans ; Male ; Membrane Proteins - chemistry ; Membrane Proteins - metabolism ; Mucins - metabolism ; N-Acetylglucosaminyltransferases - metabolism ; Phosphorylation ; Prostatic Neoplasms - metabolism ; Prostatic Neoplasms - pathology ; Sialyltransferases - metabolism ; Substrate Specificity</subject><ispartof>Molecular cancer research, 2014-12, Vol.12 (12), p.1704-1716</ispartof><rights>2014 American Association for Cancer Research.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c417t-2c5b18346a6f21a56ccf098cb83e1ffe37c9a0c06a2083b6c6c5587dac0a9f1f3</citedby><cites>FETCH-LOGICAL-c417t-2c5b18346a6f21a56ccf098cb83e1ffe37c9a0c06a2083b6c6c5587dac0a9f1f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,3356,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25086069$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Petrosyan, Armen</creatorcontrib><creatorcontrib>Holzapfel, Melissa S</creatorcontrib><creatorcontrib>Muirhead, David E</creatorcontrib><creatorcontrib>Cheng, Pi-Wan</creatorcontrib><title>Restoration of compact Golgi morphology in advanced prostate cancer enhances susceptibility to galectin-1-induced apoptosis by modifying mucin O-glycan synthesis</title><title>Molecular cancer research</title><addtitle>Mol Cancer Res</addtitle><description>Prostate cancer progression is associated with upregulation of sialyl-T antigen produced by β-galactoside α-2,3-sialyltransferase-1 (ST3Gal1) but not with core 2-associated polylactosamine despite expression of core 2 N-acetylglucosaminyltransferase-L (C2GnT-L/GCNT1). This property allows androgen-refractory prostate cancer cells to evade galectin-1 (LGALS1)-induced apoptosis, but the mechanism is not known. We have recently reported that Golgi targeting of glycosyltransferases is mediated by golgins: giantin (GOLGB1) for C2GnT-M (GCNT3) and GM130 (GOLGA2)-GRASP65 (GORASP1) or GM130-giantin for core 1 synthase. Here, we show that for Golgi targeting, C2GnT-L also uses giantin exclusively whereas ST3Gal1 uses either giantin or GM130-GRASP65. In addition, the compact Golgi morphology is detected in both androgen-sensitive prostate cancer and normal prostate cells, but fragmented Golgi and mislocalization of C2GnT-L are found in androgen-refractory cells as well as primary prostate tumors (Gleason grade 2-4). Furthermore, failure of giantin monomers to be phosphorylated and dimerized prevents Golgi from forming compact morphology and C2GnT-L from targeting the Golgi. On the other hand, ST3Gal1 reaches the Golgi by an alternate site, GM130-GRASP65. Interestingly, inhibition or knockdown of non-muscle myosin IIA (MYH9) motor protein frees up Rab6a GTPase to promote phosphorylation of giantin by polo-like kinase 3 (PLK3), which is followed by dimerization of giantin assisted by protein disulfide isomerase A3 (PDIA3), and restoration of compact Golgi morphology and targeting of C2GnT-L. Finally, the Golgi relocation of C2GnT-L in androgen-refractory cells results in their increased susceptibility to galectin-1-induced apoptosis by replacing sialyl-T antigen with polylactosamine.
This study demonstrates the importance of Golgi morphology and regulation of glycosylation and provides insight into how the Golgi influences cancer progression and metastasis.</description><subject>Apoptosis</subject><subject>Autoantigens - metabolism</subject><subject>Cell Line, Tumor</subject><subject>Dimerization</subject><subject>Galectin 1 - metabolism</subject><subject>Glycosylation</subject><subject>Golgi Apparatus - metabolism</subject><subject>Humans</subject><subject>Male</subject><subject>Membrane Proteins - chemistry</subject><subject>Membrane Proteins - metabolism</subject><subject>Mucins - metabolism</subject><subject>N-Acetylglucosaminyltransferases - metabolism</subject><subject>Phosphorylation</subject><subject>Prostatic Neoplasms - metabolism</subject><subject>Prostatic Neoplasms - pathology</subject><subject>Sialyltransferases - metabolism</subject><subject>Substrate Specificity</subject><issn>1541-7786</issn><issn>1557-3125</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkd2K1TAUhYsozjj6CppLbzJmt81PbwQ56CiMDAzH65CmSU8kTWqTDvRxfFNT5jjoVXbI2muF9VXVOyDXAFR8ANoC5lyw6--HewwtJnUH-PisugRKOW6gps_3-ay6qF6l9JOQmgBnL6uLmhLBCOsuq9_3JuW4qOxiQNEiHadZ6Yxuoh8dmuIyn6KP44ZcQGp4UEGbAc1LTFllg_R-X5AJp31IKK1Jmzm73nmXN5QjGpU3OruAAbswrPu2muOcY3IJ9VtJGJzdXBjRtOqScYdHvxVblLaQT6aoXlcvrPLJvDmfV9WPL5-Ph6_49u7m2-HTLdYt8IxrTXsQTcsUszUoyrS2pBO6F40Ba03DdaeIJkzVRDQ900xTKvigNFGdBdtcVR8ffee1n8ygTciL8nJe3KSWTUbl5P8vwZ3kGB9kW_OatVAM3p8NlvhrLbXKyZU6vFfBxDVJYE3XCi66tkj5o1SXJtNi7FMMELkDljs6uaOTBbCEVu6A5bFsvv33l097f4k2fwDu36i8</recordid><startdate>20141201</startdate><enddate>20141201</enddate><creator>Petrosyan, Armen</creator><creator>Holzapfel, Melissa S</creator><creator>Muirhead, David E</creator><creator>Cheng, Pi-Wan</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><scope>5PM</scope></search><sort><creationdate>20141201</creationdate><title>Restoration of compact Golgi morphology in advanced prostate cancer enhances susceptibility to galectin-1-induced apoptosis by modifying mucin O-glycan synthesis</title><author>Petrosyan, Armen ; Holzapfel, Melissa S ; Muirhead, David E ; Cheng, Pi-Wan</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c417t-2c5b18346a6f21a56ccf098cb83e1ffe37c9a0c06a2083b6c6c5587dac0a9f1f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Apoptosis</topic><topic>Autoantigens - metabolism</topic><topic>Cell Line, Tumor</topic><topic>Dimerization</topic><topic>Galectin 1 - metabolism</topic><topic>Glycosylation</topic><topic>Golgi Apparatus - metabolism</topic><topic>Humans</topic><topic>Male</topic><topic>Membrane Proteins - chemistry</topic><topic>Membrane Proteins - metabolism</topic><topic>Mucins - metabolism</topic><topic>N-Acetylglucosaminyltransferases - metabolism</topic><topic>Phosphorylation</topic><topic>Prostatic Neoplasms - metabolism</topic><topic>Prostatic Neoplasms - pathology</topic><topic>Sialyltransferases - metabolism</topic><topic>Substrate Specificity</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Petrosyan, Armen</creatorcontrib><creatorcontrib>Holzapfel, Melissa S</creatorcontrib><creatorcontrib>Muirhead, David E</creatorcontrib><creatorcontrib>Cheng, Pi-Wan</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><collection>PubMed Central (Full Participant titles)</collection><jtitle>Molecular cancer research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Petrosyan, Armen</au><au>Holzapfel, Melissa S</au><au>Muirhead, David E</au><au>Cheng, Pi-Wan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Restoration of compact Golgi morphology in advanced prostate cancer enhances susceptibility to galectin-1-induced apoptosis by modifying mucin O-glycan synthesis</atitle><jtitle>Molecular cancer research</jtitle><addtitle>Mol Cancer Res</addtitle><date>2014-12-01</date><risdate>2014</risdate><volume>12</volume><issue>12</issue><spage>1704</spage><epage>1716</epage><pages>1704-1716</pages><issn>1541-7786</issn><eissn>1557-3125</eissn><abstract>Prostate cancer progression is associated with upregulation of sialyl-T antigen produced by β-galactoside α-2,3-sialyltransferase-1 (ST3Gal1) but not with core 2-associated polylactosamine despite expression of core 2 N-acetylglucosaminyltransferase-L (C2GnT-L/GCNT1). This property allows androgen-refractory prostate cancer cells to evade galectin-1 (LGALS1)-induced apoptosis, but the mechanism is not known. We have recently reported that Golgi targeting of glycosyltransferases is mediated by golgins: giantin (GOLGB1) for C2GnT-M (GCNT3) and GM130 (GOLGA2)-GRASP65 (GORASP1) or GM130-giantin for core 1 synthase. Here, we show that for Golgi targeting, C2GnT-L also uses giantin exclusively whereas ST3Gal1 uses either giantin or GM130-GRASP65. In addition, the compact Golgi morphology is detected in both androgen-sensitive prostate cancer and normal prostate cells, but fragmented Golgi and mislocalization of C2GnT-L are found in androgen-refractory cells as well as primary prostate tumors (Gleason grade 2-4). Furthermore, failure of giantin monomers to be phosphorylated and dimerized prevents Golgi from forming compact morphology and C2GnT-L from targeting the Golgi. On the other hand, ST3Gal1 reaches the Golgi by an alternate site, GM130-GRASP65. Interestingly, inhibition or knockdown of non-muscle myosin IIA (MYH9) motor protein frees up Rab6a GTPase to promote phosphorylation of giantin by polo-like kinase 3 (PLK3), which is followed by dimerization of giantin assisted by protein disulfide isomerase A3 (PDIA3), and restoration of compact Golgi morphology and targeting of C2GnT-L. Finally, the Golgi relocation of C2GnT-L in androgen-refractory cells results in their increased susceptibility to galectin-1-induced apoptosis by replacing sialyl-T antigen with polylactosamine.
This study demonstrates the importance of Golgi morphology and regulation of glycosylation and provides insight into how the Golgi influences cancer progression and metastasis.</abstract><cop>United States</cop><pmid>25086069</pmid><doi>10.1158/1541-7786.MCR-14-0291-T</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Apoptosis Autoantigens - metabolism Cell Line, Tumor Dimerization Galectin 1 - metabolism Glycosylation Golgi Apparatus - metabolism Humans Male Membrane Proteins - chemistry Membrane Proteins - metabolism Mucins - metabolism N-Acetylglucosaminyltransferases - metabolism Phosphorylation Prostatic Neoplasms - metabolism Prostatic Neoplasms - pathology Sialyltransferases - metabolism Substrate Specificity |
title | Restoration of compact Golgi morphology in advanced prostate cancer enhances susceptibility to galectin-1-induced apoptosis by modifying mucin O-glycan synthesis |
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