Abnormal lysosomal trafficking and enhanced exosomal export of cisplatin in drug-resistant human ovarian carcinoma cells
Previous work has shown that cisplatin (CDDP) becomes concentrated in lysosomes, and that acquired resistance to CDDP is associated with abnormalities of protein trafficking and secretion. The lysosomal compartment in CDDP-sensitive 2008 human ovarian carcinoma cells was compared with that in CDDP-r...
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| Veröffentlicht in: | Molecular cancer therapeutics 2005-10, Vol.4 (10), p.1595-1604 |
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| creator | Safaei, Roohangiz Larson, Barrett J Cheng, Timothy C Gibson, Michael A Otani, Shinji Naerdemann, Wiltrud Howell, Stephen B |
| description | Previous work has shown that cisplatin (CDDP) becomes concentrated in lysosomes, and that acquired resistance to CDDP is associated
with abnormalities of protein trafficking and secretion. The lysosomal compartment in CDDP-sensitive 2008 human ovarian carcinoma
cells was compared with that in CDDP-resistant 2008/C13*5.25 subline using deconvoluting imaging and specific dyes and antibodies.
The lysosomal compartment in CDDP-resistant cells was reduced to just 40% of that in the parental CDDP-sensitive cells ( P < 0.002). This was accompanied by a reduced expression of the lysosome-associated proteins 1 and 2 (LAMP1 and LAMP2) as determined
by both microscopy and Western blot analysis. The CDDP-resistant cells released more protein as exosomes and Western blot
analysis revealed that these exosomes contained substantially more LAMP1 than those released by the CDDP-sensitive cells.
Following loading of the whole cell with CDDP, the exosomes released from 2008/C13*5.25 cells contained 2.6-fold more platinum
than those released from sensitive cells. Enhanced exosomal export was accompanied by higher exosomal levels of the putative
CDDP export transporters MRP2, ATP7A, and ATP7B. Expression profiling identified significant increases in the expression of
several genes whose products function in membrane fusion and vesicle trafficking. This study shows that the lysosomal compartment
of human ovarian carcinoma cells selected for stable resistance to CDDP is markedly reduced in size, and that these cells
abnormally sort some lysosomal proteins and the putative CDDP transporters into an exosomal pathway that also exports CDDP. |
| doi_str_mv | 10.1158/1535-7163.MCT-05-0102 |
| format | Article |
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with abnormalities of protein trafficking and secretion. The lysosomal compartment in CDDP-sensitive 2008 human ovarian carcinoma
cells was compared with that in CDDP-resistant 2008/C13*5.25 subline using deconvoluting imaging and specific dyes and antibodies.
The lysosomal compartment in CDDP-resistant cells was reduced to just 40% of that in the parental CDDP-sensitive cells ( P < 0.002). This was accompanied by a reduced expression of the lysosome-associated proteins 1 and 2 (LAMP1 and LAMP2) as determined
by both microscopy and Western blot analysis. The CDDP-resistant cells released more protein as exosomes and Western blot
analysis revealed that these exosomes contained substantially more LAMP1 than those released by the CDDP-sensitive cells.
Following loading of the whole cell with CDDP, the exosomes released from 2008/C13*5.25 cells contained 2.6-fold more platinum
than those released from sensitive cells. Enhanced exosomal export was accompanied by higher exosomal levels of the putative
CDDP export transporters MRP2, ATP7A, and ATP7B. Expression profiling identified significant increases in the expression of
several genes whose products function in membrane fusion and vesicle trafficking. This study shows that the lysosomal compartment
of human ovarian carcinoma cells selected for stable resistance to CDDP is markedly reduced in size, and that these cells
abnormally sort some lysosomal proteins and the putative CDDP transporters into an exosomal pathway that also exports CDDP.</description><identifier>ISSN: 1535-7163</identifier><identifier>EISSN: 1538-8514</identifier><identifier>DOI: 10.1158/1535-7163.MCT-05-0102</identifier><identifier>PMID: 16227410</identifier><language>eng</language><publisher>United States: American Association for Cancer Research</publisher><subject>Animals ; ATP7A ; ATP7B ; Cisplatin ; Cisplatin - pharmacokinetics ; Cisplatin - pharmacology ; Drug Resistance ; Drug Resistance, Neoplasm ; exosome ; Female ; Humans ; Lysosomal-Associated Membrane Protein 1 - metabolism ; Lysosomal-Associated Membrane Protein 2 - metabolism ; lysosome ; Lysosomes - metabolism ; Ovarian Neoplasms - drug therapy ; Ovarian Neoplasms - metabolism ; Secretory Vesicles - metabolism ; Tumor Cells, Cultured</subject><ispartof>Molecular cancer therapeutics, 2005-10, Vol.4 (10), p.1595-1604</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c425t-4bb9749ebbb36e88b8fc92cd5f4ff3fd61412565d7c637281f0f39a16126eec73</citedby><cites>FETCH-LOGICAL-c425t-4bb9749ebbb36e88b8fc92cd5f4ff3fd61412565d7c637281f0f39a16126eec73</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,3342,27903,27904</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16227410$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Safaei, Roohangiz</creatorcontrib><creatorcontrib>Larson, Barrett J</creatorcontrib><creatorcontrib>Cheng, Timothy C</creatorcontrib><creatorcontrib>Gibson, Michael A</creatorcontrib><creatorcontrib>Otani, Shinji</creatorcontrib><creatorcontrib>Naerdemann, Wiltrud</creatorcontrib><creatorcontrib>Howell, Stephen B</creatorcontrib><title>Abnormal lysosomal trafficking and enhanced exosomal export of cisplatin in drug-resistant human ovarian carcinoma cells</title><title>Molecular cancer therapeutics</title><addtitle>Mol Cancer Ther</addtitle><description>Previous work has shown that cisplatin (CDDP) becomes concentrated in lysosomes, and that acquired resistance to CDDP is associated
with abnormalities of protein trafficking and secretion. The lysosomal compartment in CDDP-sensitive 2008 human ovarian carcinoma
cells was compared with that in CDDP-resistant 2008/C13*5.25 subline using deconvoluting imaging and specific dyes and antibodies.
The lysosomal compartment in CDDP-resistant cells was reduced to just 40% of that in the parental CDDP-sensitive cells ( P < 0.002). This was accompanied by a reduced expression of the lysosome-associated proteins 1 and 2 (LAMP1 and LAMP2) as determined
by both microscopy and Western blot analysis. The CDDP-resistant cells released more protein as exosomes and Western blot
analysis revealed that these exosomes contained substantially more LAMP1 than those released by the CDDP-sensitive cells.
Following loading of the whole cell with CDDP, the exosomes released from 2008/C13*5.25 cells contained 2.6-fold more platinum
than those released from sensitive cells. Enhanced exosomal export was accompanied by higher exosomal levels of the putative
CDDP export transporters MRP2, ATP7A, and ATP7B. Expression profiling identified significant increases in the expression of
several genes whose products function in membrane fusion and vesicle trafficking. This study shows that the lysosomal compartment
of human ovarian carcinoma cells selected for stable resistance to CDDP is markedly reduced in size, and that these cells
abnormally sort some lysosomal proteins and the putative CDDP transporters into an exosomal pathway that also exports CDDP.</description><subject>Animals</subject><subject>ATP7A</subject><subject>ATP7B</subject><subject>Cisplatin</subject><subject>Cisplatin - pharmacokinetics</subject><subject>Cisplatin - pharmacology</subject><subject>Drug Resistance</subject><subject>Drug Resistance, Neoplasm</subject><subject>exosome</subject><subject>Female</subject><subject>Humans</subject><subject>Lysosomal-Associated Membrane Protein 1 - metabolism</subject><subject>Lysosomal-Associated Membrane Protein 2 - metabolism</subject><subject>lysosome</subject><subject>Lysosomes - metabolism</subject><subject>Ovarian Neoplasms - drug therapy</subject><subject>Ovarian Neoplasms - metabolism</subject><subject>Secretory Vesicles - metabolism</subject><subject>Tumor Cells, Cultured</subject><issn>1535-7163</issn><issn>1538-8514</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2005</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkM1u3CAURlGVqvlpH6ERqygbp1wwGC-jUdJWStVNukYYw5jEhgnY6eTtizMjVUK6n9D5uOgg9BXIDQCX34AzXjUg2M2vzWNFeEWA0A_orNzLSnKoT97zgTlF5zk_EQKypfAJnYKgtKmBnKH9bRdimvSIx7ccc1zTnLRz3jz7sMU69NiGQQdjS9gfCbvfxTTj6LDxeTfq2QdcTp-WbZVs9nnWYcbDMumA46tOvkyjk_Gh1LGx45g_o49Oj9l-Oc4L9Of-7nHzo3r4_f3n5vahMjXlc1V3XdvUre26jgkrZSedaanpuaudY64XUAPlgveNEayhEhxxrNUggAprTcMu0NXh3V2KL4vNs5p8Xn-gg41LVkKKtmVcFpAfQJNizsk6tUt-0ulNAVGrcrXqVKtOVZQrwtWqvPQujwuWbrL9_9bRcQGuD8Dgt8Nfn6wyq85URNniZFD1-wbecvYPSr2N0Q</recordid><startdate>20051001</startdate><enddate>20051001</enddate><creator>Safaei, Roohangiz</creator><creator>Larson, Barrett J</creator><creator>Cheng, Timothy C</creator><creator>Gibson, Michael A</creator><creator>Otani, Shinji</creator><creator>Naerdemann, Wiltrud</creator><creator>Howell, Stephen B</creator><general>American Association for Cancer Research</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>20051001</creationdate><title>Abnormal lysosomal trafficking and enhanced exosomal export of cisplatin in drug-resistant human ovarian carcinoma cells</title><author>Safaei, Roohangiz ; Larson, Barrett J ; Cheng, Timothy C ; Gibson, Michael A ; Otani, Shinji ; Naerdemann, Wiltrud ; Howell, Stephen B</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c425t-4bb9749ebbb36e88b8fc92cd5f4ff3fd61412565d7c637281f0f39a16126eec73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2005</creationdate><topic>Animals</topic><topic>ATP7A</topic><topic>ATP7B</topic><topic>Cisplatin</topic><topic>Cisplatin - pharmacokinetics</topic><topic>Cisplatin - pharmacology</topic><topic>Drug Resistance</topic><topic>Drug Resistance, Neoplasm</topic><topic>exosome</topic><topic>Female</topic><topic>Humans</topic><topic>Lysosomal-Associated Membrane Protein 1 - metabolism</topic><topic>Lysosomal-Associated Membrane Protein 2 - metabolism</topic><topic>lysosome</topic><topic>Lysosomes - metabolism</topic><topic>Ovarian Neoplasms - drug therapy</topic><topic>Ovarian Neoplasms - metabolism</topic><topic>Secretory Vesicles - metabolism</topic><topic>Tumor Cells, Cultured</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Safaei, Roohangiz</creatorcontrib><creatorcontrib>Larson, Barrett J</creatorcontrib><creatorcontrib>Cheng, Timothy C</creatorcontrib><creatorcontrib>Gibson, Michael A</creatorcontrib><creatorcontrib>Otani, Shinji</creatorcontrib><creatorcontrib>Naerdemann, Wiltrud</creatorcontrib><creatorcontrib>Howell, Stephen B</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>Molecular cancer therapeutics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Safaei, Roohangiz</au><au>Larson, Barrett J</au><au>Cheng, Timothy C</au><au>Gibson, Michael A</au><au>Otani, Shinji</au><au>Naerdemann, Wiltrud</au><au>Howell, Stephen B</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Abnormal lysosomal trafficking and enhanced exosomal export of cisplatin in drug-resistant human ovarian carcinoma cells</atitle><jtitle>Molecular cancer therapeutics</jtitle><addtitle>Mol Cancer Ther</addtitle><date>2005-10-01</date><risdate>2005</risdate><volume>4</volume><issue>10</issue><spage>1595</spage><epage>1604</epage><pages>1595-1604</pages><issn>1535-7163</issn><eissn>1538-8514</eissn><abstract>Previous work has shown that cisplatin (CDDP) becomes concentrated in lysosomes, and that acquired resistance to CDDP is associated
with abnormalities of protein trafficking and secretion. The lysosomal compartment in CDDP-sensitive 2008 human ovarian carcinoma
cells was compared with that in CDDP-resistant 2008/C13*5.25 subline using deconvoluting imaging and specific dyes and antibodies.
The lysosomal compartment in CDDP-resistant cells was reduced to just 40% of that in the parental CDDP-sensitive cells ( P < 0.002). This was accompanied by a reduced expression of the lysosome-associated proteins 1 and 2 (LAMP1 and LAMP2) as determined
by both microscopy and Western blot analysis. The CDDP-resistant cells released more protein as exosomes and Western blot
analysis revealed that these exosomes contained substantially more LAMP1 than those released by the CDDP-sensitive cells.
Following loading of the whole cell with CDDP, the exosomes released from 2008/C13*5.25 cells contained 2.6-fold more platinum
than those released from sensitive cells. Enhanced exosomal export was accompanied by higher exosomal levels of the putative
CDDP export transporters MRP2, ATP7A, and ATP7B. Expression profiling identified significant increases in the expression of
several genes whose products function in membrane fusion and vesicle trafficking. This study shows that the lysosomal compartment
of human ovarian carcinoma cells selected for stable resistance to CDDP is markedly reduced in size, and that these cells
abnormally sort some lysosomal proteins and the putative CDDP transporters into an exosomal pathway that also exports CDDP.</abstract><cop>United States</cop><pub>American Association for Cancer Research</pub><pmid>16227410</pmid><doi>10.1158/1535-7163.MCT-05-0102</doi><tpages>10</tpages></addata></record> |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; American Association for Cancer Research |
| subjects | Animals ATP7A ATP7B Cisplatin Cisplatin - pharmacokinetics Cisplatin - pharmacology Drug Resistance Drug Resistance, Neoplasm exosome Female Humans Lysosomal-Associated Membrane Protein 1 - metabolism Lysosomal-Associated Membrane Protein 2 - metabolism lysosome Lysosomes - metabolism Ovarian Neoplasms - drug therapy Ovarian Neoplasms - metabolism Secretory Vesicles - metabolism Tumor Cells, Cultured |
| title | Abnormal lysosomal trafficking and enhanced exosomal export of cisplatin in drug-resistant human ovarian carcinoma cells |
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