Proteomic analysis reveals a novel role for the actin cytoskeleton in vincristine resistant childhood leukemia - An in vivo study
Intrinsic or acquired resistance to vincristine (VCR), an antimicrotubule agent used in the treatment of childhood acute lymphoblastic leukemia (ALL), is a major clinical problem. Using a clinically relevant NOD/SCID mouse xenograft model of ALL, we established that alterations in the actin and tubu...
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| Veröffentlicht in: | Proteomics (Weinheim) 2006-03, Vol.6 (5), p.1681-1694 |
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| creator | Verrills, Nicole M. Liem, Natalia L. Liaw, Tracy Y. E. Hood, Brian D. Lock, Richard B. Kavallaris, Maria |
| description | Intrinsic or acquired resistance to vincristine (VCR), an antimicrotubule agent used in the treatment of childhood acute lymphoblastic leukemia (ALL), is a major clinical problem. Using a clinically relevant NOD/SCID mouse xenograft model of ALL, we established that alterations in the actin and tubulin cytoskeleton are involved in in vivo VCR resistance. Altered protein expression between VCR‐sensitive ALL xenografts, and xenografts with intrinsic or acquired VCR resistance, was identified using 2‐D DIGE coupled with MS. Of the 19 proteins displaying altered expression, 11 are associated with the actin cytoskeleton. Altered expression of the actin‐ and/or tubulin‐binding proteins gelsolin, moesin, ezrin, tropomyosin, CAP‐G, HSP27, HSP70, TCP‐1, and stathmin were associated with in vivo VCR resistance. The actin‐regulating protein gelsolin was increased in both acquired and resistant leukemia as confirmed by immunoblotting and gene expression. The major cytoskeletal protein, γ‐actin, was down‐regulated in the VCR‐resistant leukemia xenografts; in contrast, there was no significant change in β‐actin expression. This study provides the first evidence for a role of the actin cytoskeleton in intrinsic and acquired in vivo antimicrotubule drug resistance in childhood leukemia and highlights the power of 2‐D DIGE for the discovery of resistance markers, pharmacoproteomics, and signaling pathways in cancer. |
| doi_str_mv | 10.1002/pmic.200500417 |
| format | Article |
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E. ; Hood, Brian D. ; Lock, Richard B. ; Kavallaris, Maria</creator><creatorcontrib>Verrills, Nicole M. ; Liem, Natalia L. ; Liaw, Tracy Y. E. ; Hood, Brian D. ; Lock, Richard B. ; Kavallaris, Maria</creatorcontrib><description>Intrinsic or acquired resistance to vincristine (VCR), an antimicrotubule agent used in the treatment of childhood acute lymphoblastic leukemia (ALL), is a major clinical problem. Using a clinically relevant NOD/SCID mouse xenograft model of ALL, we established that alterations in the actin and tubulin cytoskeleton are involved in in vivo VCR resistance. Altered protein expression between VCR‐sensitive ALL xenografts, and xenografts with intrinsic or acquired VCR resistance, was identified using 2‐D DIGE coupled with MS. Of the 19 proteins displaying altered expression, 11 are associated with the actin cytoskeleton. Altered expression of the actin‐ and/or tubulin‐binding proteins gelsolin, moesin, ezrin, tropomyosin, CAP‐G, HSP27, HSP70, TCP‐1, and stathmin were associated with in vivo VCR resistance. The actin‐regulating protein gelsolin was increased in both acquired and resistant leukemia as confirmed by immunoblotting and gene expression. The major cytoskeletal protein, γ‐actin, was down‐regulated in the VCR‐resistant leukemia xenografts; in contrast, there was no significant change in β‐actin expression. This study provides the first evidence for a role of the actin cytoskeleton in intrinsic and acquired in vivo antimicrotubule drug resistance in childhood leukemia and highlights the power of 2‐D DIGE for the discovery of resistance markers, pharmacoproteomics, and signaling pathways in cancer.</description><identifier>ISSN: 1615-9853</identifier><identifier>EISSN: 1615-9861</identifier><identifier>DOI: 10.1002/pmic.200500417</identifier><identifier>PMID: 16456880</identifier><language>eng</language><publisher>Weinheim: WILEY-VCH Verlag</publisher><subject>Actin ; Actins - chemistry ; Actins - metabolism ; Analytical, structural and metabolic biochemistry ; Animals ; Antineoplastic Agents, Phytogenic - therapeutic use ; Biological and medical sciences ; Child ; Cytoskeleton - chemistry ; Cytoskeleton - metabolism ; Drug resistance ; Drug Resistance, Neoplasm ; Electrophoresis, Gel, Two-Dimensional ; Fundamental and applied biological sciences. 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E.</creatorcontrib><creatorcontrib>Hood, Brian D.</creatorcontrib><creatorcontrib>Lock, Richard B.</creatorcontrib><creatorcontrib>Kavallaris, Maria</creatorcontrib><title>Proteomic analysis reveals a novel role for the actin cytoskeleton in vincristine resistant childhood leukemia - An in vivo study</title><title>Proteomics (Weinheim)</title><addtitle>Proteomics</addtitle><description>Intrinsic or acquired resistance to vincristine (VCR), an antimicrotubule agent used in the treatment of childhood acute lymphoblastic leukemia (ALL), is a major clinical problem. Using a clinically relevant NOD/SCID mouse xenograft model of ALL, we established that alterations in the actin and tubulin cytoskeleton are involved in in vivo VCR resistance. Altered protein expression between VCR‐sensitive ALL xenografts, and xenografts with intrinsic or acquired VCR resistance, was identified using 2‐D DIGE coupled with MS. Of the 19 proteins displaying altered expression, 11 are associated with the actin cytoskeleton. Altered expression of the actin‐ and/or tubulin‐binding proteins gelsolin, moesin, ezrin, tropomyosin, CAP‐G, HSP27, HSP70, TCP‐1, and stathmin were associated with in vivo VCR resistance. The actin‐regulating protein gelsolin was increased in both acquired and resistant leukemia as confirmed by immunoblotting and gene expression. The major cytoskeletal protein, γ‐actin, was down‐regulated in the VCR‐resistant leukemia xenografts; in contrast, there was no significant change in β‐actin expression. This study provides the first evidence for a role of the actin cytoskeleton in intrinsic and acquired in vivo antimicrotubule drug resistance in childhood leukemia and highlights the power of 2‐D DIGE for the discovery of resistance markers, pharmacoproteomics, and signaling pathways in cancer.</description><subject>Actin</subject><subject>Actins - chemistry</subject><subject>Actins - metabolism</subject><subject>Analytical, structural and metabolic biochemistry</subject><subject>Animals</subject><subject>Antineoplastic Agents, Phytogenic - therapeutic use</subject><subject>Biological and medical sciences</subject><subject>Child</subject><subject>Cytoskeleton - chemistry</subject><subject>Cytoskeleton - metabolism</subject><subject>Drug resistance</subject><subject>Drug Resistance, Neoplasm</subject><subject>Electrophoresis, Gel, Two-Dimensional</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Hematologic and hematopoietic diseases</subject><subject>Humans</subject><subject>Leukemia</subject><subject>Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, SCID</subject><subject>Microtubule Proteins - chemistry</subject><subject>Microtubule Proteins - metabolism</subject><subject>Miscellaneous</subject><subject>Molecular Sequence Data</subject><subject>Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy</subject><subject>Precursor Cell Lymphoblastic Leukemia-Lymphoma - metabolism</subject><subject>Proteins</subject><subject>Proteome - analysis</subject><subject>Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization</subject><subject>Transplantation, Heterologous</subject><subject>Vincristine</subject><issn>1615-9853</issn><issn>1615-9861</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2006</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkUFv1DAQhSMEoqVw5Yh8gVsWO3Hi-FhWUCq1UCRQuVkTe6I168RbO1nIkX-Oq4223Hoaj_y9N6N5Wfaa0RWjtHi_661eFZRWlHImnmSnrGZVLpuaPT2-q_IkexHjL0qZaKR4np2wmld109DT7O9N8CP65EJgADdHG0nAPYKLBMjg9-hI8A5J5wMZN0hAj3Ygeh593KLD0Q8k9Xs76GBj-sIkTyYjDCPRG-vMxntDHE5b7C2QnJwvgr0ncZzM_DJ71qVp-GqpZ9mPTx-_rz_nV18vLtfnV7nmvBA5Fy22LYjacMFKI1HLsi4ELxkTHKAWhWFcVm0DwHhNwTRGgO4MLWXHdCvKs-zdwXcX_N2EcVS9jRqdgwH9FFUtRNFQKR8FmeQ83ZolcHUAdfAxBuzULtgewqwYVffpqPt01DGdJHizOE9tj-YBX-JIwNsFgKjBdQEGbeMDJypBC1kmTh6439bh_MhYdXN9uf5_ifygTSHhn6MWwjadoBSVuv1yoX7e8utv6-aDouU_7M26HQ</recordid><startdate>20060301</startdate><enddate>20060301</enddate><creator>Verrills, Nicole M.</creator><creator>Liem, Natalia L.</creator><creator>Liaw, Tracy Y. 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E. ; Hood, Brian D. ; Lock, Richard B. ; Kavallaris, Maria</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4427-47bebba76d4713d9ec93627431174aa672d1495b8aa1460ad8d7acfd039f1cb73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2006</creationdate><topic>Actin</topic><topic>Actins - chemistry</topic><topic>Actins - metabolism</topic><topic>Analytical, structural and metabolic biochemistry</topic><topic>Animals</topic><topic>Antineoplastic Agents, Phytogenic - therapeutic use</topic><topic>Biological and medical sciences</topic><topic>Child</topic><topic>Cytoskeleton - chemistry</topic><topic>Cytoskeleton - metabolism</topic><topic>Drug resistance</topic><topic>Drug Resistance, Neoplasm</topic><topic>Electrophoresis, Gel, Two-Dimensional</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Hematologic and hematopoietic diseases</topic><topic>Humans</topic><topic>Leukemia</topic><topic>Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, SCID</topic><topic>Microtubule Proteins - chemistry</topic><topic>Microtubule Proteins - metabolism</topic><topic>Miscellaneous</topic><topic>Molecular Sequence Data</topic><topic>Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy</topic><topic>Precursor Cell Lymphoblastic Leukemia-Lymphoma - metabolism</topic><topic>Proteins</topic><topic>Proteome - analysis</topic><topic>Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization</topic><topic>Transplantation, Heterologous</topic><topic>Vincristine</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Verrills, Nicole M.</creatorcontrib><creatorcontrib>Liem, Natalia L.</creatorcontrib><creatorcontrib>Liaw, Tracy Y. E.</creatorcontrib><creatorcontrib>Hood, Brian D.</creatorcontrib><creatorcontrib>Lock, Richard B.</creatorcontrib><creatorcontrib>Kavallaris, Maria</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>Biotechnology Research Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Proteomics (Weinheim)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Verrills, Nicole M.</au><au>Liem, Natalia L.</au><au>Liaw, Tracy Y. E.</au><au>Hood, Brian D.</au><au>Lock, Richard B.</au><au>Kavallaris, Maria</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Proteomic analysis reveals a novel role for the actin cytoskeleton in vincristine resistant childhood leukemia - An in vivo study</atitle><jtitle>Proteomics (Weinheim)</jtitle><addtitle>Proteomics</addtitle><date>2006-03-01</date><risdate>2006</risdate><volume>6</volume><issue>5</issue><spage>1681</spage><epage>1694</epage><pages>1681-1694</pages><issn>1615-9853</issn><eissn>1615-9861</eissn><abstract>Intrinsic or acquired resistance to vincristine (VCR), an antimicrotubule agent used in the treatment of childhood acute lymphoblastic leukemia (ALL), is a major clinical problem. Using a clinically relevant NOD/SCID mouse xenograft model of ALL, we established that alterations in the actin and tubulin cytoskeleton are involved in in vivo VCR resistance. Altered protein expression between VCR‐sensitive ALL xenografts, and xenografts with intrinsic or acquired VCR resistance, was identified using 2‐D DIGE coupled with MS. Of the 19 proteins displaying altered expression, 11 are associated with the actin cytoskeleton. Altered expression of the actin‐ and/or tubulin‐binding proteins gelsolin, moesin, ezrin, tropomyosin, CAP‐G, HSP27, HSP70, TCP‐1, and stathmin were associated with in vivo VCR resistance. The actin‐regulating protein gelsolin was increased in both acquired and resistant leukemia as confirmed by immunoblotting and gene expression. The major cytoskeletal protein, γ‐actin, was down‐regulated in the VCR‐resistant leukemia xenografts; in contrast, there was no significant change in β‐actin expression. This study provides the first evidence for a role of the actin cytoskeleton in intrinsic and acquired in vivo antimicrotubule drug resistance in childhood leukemia and highlights the power of 2‐D DIGE for the discovery of resistance markers, pharmacoproteomics, and signaling pathways in cancer.</abstract><cop>Weinheim</cop><pub>WILEY-VCH Verlag</pub><pmid>16456880</pmid><doi>10.1002/pmic.200500417</doi><tpages>14</tpages></addata></record> |
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| subjects | Actin Actins - chemistry Actins - metabolism Analytical, structural and metabolic biochemistry Animals Antineoplastic Agents, Phytogenic - therapeutic use Biological and medical sciences Child Cytoskeleton - chemistry Cytoskeleton - metabolism Drug resistance Drug Resistance, Neoplasm Electrophoresis, Gel, Two-Dimensional Fundamental and applied biological sciences. Psychology Hematologic and hematopoietic diseases Humans Leukemia Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis Medical sciences Mice Mice, SCID Microtubule Proteins - chemistry Microtubule Proteins - metabolism Miscellaneous Molecular Sequence Data Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy Precursor Cell Lymphoblastic Leukemia-Lymphoma - metabolism Proteins Proteome - analysis Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization Transplantation, Heterologous Vincristine |
| title | Proteomic analysis reveals a novel role for the actin cytoskeleton in vincristine resistant childhood leukemia - An in vivo study |
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