High-Throughput Screening of Myxoid Liposarcoma Cell Lines: Survivin Is Essential for Tumor Growth
Myxoid liposarcoma (MLS) is a soft tissue sarcoma characterized by a recurrent t(12;16) translocation. Although tumors are initially radio- and chemosensitive, the management of inoperable or metastatic MLS can be challenging. Therefore, our aim was to identify novel targets for systemic therapy. We...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2017-08-01
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| Series: | Translational Oncology |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1936523317300803 |
| _version_ | 1811270412600868864 |
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| author | Marieke A. de Graaff Shruti Malu Irma Guardiola Alwine B. Kruisselbrink Yvonne de Jong Willem E. Corver H. Gelderblom Patrick Hwu Torsten O. Nielsen Alexander J. Lazar Neeta Somaiah Judith V.M.G. Bovée |
| author_facet | Marieke A. de Graaff Shruti Malu Irma Guardiola Alwine B. Kruisselbrink Yvonne de Jong Willem E. Corver H. Gelderblom Patrick Hwu Torsten O. Nielsen Alexander J. Lazar Neeta Somaiah Judith V.M.G. Bovée |
| author_sort | Marieke A. de Graaff |
| collection | DOAJ |
| description | Myxoid liposarcoma (MLS) is a soft tissue sarcoma characterized by a recurrent t(12;16) translocation. Although tumors are initially radio- and chemosensitive, the management of inoperable or metastatic MLS can be challenging. Therefore, our aim was to identify novel targets for systemic therapy. We performed an in vitro high-throughput drug screen using three MLS cell lines (402091, 1765092, DL-221), which were treated with 273 different drugs at four different concentrations. Cell lines and tissue microarrays were used for validation. As expected, all cell lines revealed a strong growth inhibition to conventional chemotherapeutic agents, such as anthracyclines and taxanes. A good response was observed to compounds interfering with Src and the mTOR pathway, which are known to be affected in these tumors. Moreover, BIRC5 was important for MLS survival because a strong inhibitory effect was seen at low concentration using the survivin inhibitor YM155, and siRNA for BIRC5 decreased cell viability. Immunohistochemistry revealed abundant expression of survivin restricted to the nucleus in all 32 tested primary tumor specimens. Inhibition of survivin in 402-91 and 1765-92 by YM155 increased the percentage S-phase but did not induce apoptosis, which warrants further investigation before application in the treatment of metastatic MLS. Thus, using a 273-compound drug screen, we confirmed previously identified targets (mTOR, Src) in MLS and demonstrate survivin as essential for MLS survival. |
| first_indexed | 2024-04-12T22:00:18Z |
| format | Article |
| id | doaj.art-35953edcb14f4aa6a63affcf63c90da0 |
| institution | Directory Open Access Journal |
| issn | 1936-5233 1944-7124 |
| language | English |
| last_indexed | 2024-04-12T22:00:18Z |
| publishDate | 2017-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Translational Oncology |
| spelling | doaj.art-35953edcb14f4aa6a63affcf63c90da02022-12-22T03:15:08ZengElsevierTranslational Oncology1936-52331944-71242017-08-0110454655410.1016/j.tranon.2017.05.007High-Throughput Screening of Myxoid Liposarcoma Cell Lines: Survivin Is Essential for Tumor GrowthMarieke A. de Graaff0Shruti Malu1Irma Guardiola2Alwine B. Kruisselbrink3Yvonne de Jong4Willem E. Corver5H. Gelderblom6Patrick Hwu7Torsten O. Nielsen8Alexander J. Lazar9Neeta Somaiah10Judith V.M.G. Bovée11Department of Pathology, Leiden University Medical Center, Leiden, the NetherlandsDepartment of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USADepartment of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USADepartment of Pathology, Leiden University Medical Center, Leiden, the NetherlandsDepartment of Pathology, Leiden University Medical Center, Leiden, the NetherlandsDepartment of Pathology, Leiden University Medical Center, Leiden, the NetherlandsDepartment of Medical Oncology, Leiden University Medical Center, Leiden, the NetherlandsDepartment of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USADepartment of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, CanadaDepartment of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USADepartment of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USADepartment of Pathology, Leiden University Medical Center, Leiden, the NetherlandsMyxoid liposarcoma (MLS) is a soft tissue sarcoma characterized by a recurrent t(12;16) translocation. Although tumors are initially radio- and chemosensitive, the management of inoperable or metastatic MLS can be challenging. Therefore, our aim was to identify novel targets for systemic therapy. We performed an in vitro high-throughput drug screen using three MLS cell lines (402091, 1765092, DL-221), which were treated with 273 different drugs at four different concentrations. Cell lines and tissue microarrays were used for validation. As expected, all cell lines revealed a strong growth inhibition to conventional chemotherapeutic agents, such as anthracyclines and taxanes. A good response was observed to compounds interfering with Src and the mTOR pathway, which are known to be affected in these tumors. Moreover, BIRC5 was important for MLS survival because a strong inhibitory effect was seen at low concentration using the survivin inhibitor YM155, and siRNA for BIRC5 decreased cell viability. Immunohistochemistry revealed abundant expression of survivin restricted to the nucleus in all 32 tested primary tumor specimens. Inhibition of survivin in 402-91 and 1765-92 by YM155 increased the percentage S-phase but did not induce apoptosis, which warrants further investigation before application in the treatment of metastatic MLS. Thus, using a 273-compound drug screen, we confirmed previously identified targets (mTOR, Src) in MLS and demonstrate survivin as essential for MLS survival.http://www.sciencedirect.com/science/article/pii/S1936523317300803 |
| spellingShingle | Marieke A. de Graaff Shruti Malu Irma Guardiola Alwine B. Kruisselbrink Yvonne de Jong Willem E. Corver H. Gelderblom Patrick Hwu Torsten O. Nielsen Alexander J. Lazar Neeta Somaiah Judith V.M.G. Bovée High-Throughput Screening of Myxoid Liposarcoma Cell Lines: Survivin Is Essential for Tumor Growth Translational Oncology |
| title | High-Throughput Screening of Myxoid Liposarcoma Cell Lines: Survivin Is Essential for Tumor Growth |
| title_full | High-Throughput Screening of Myxoid Liposarcoma Cell Lines: Survivin Is Essential for Tumor Growth |
| title_fullStr | High-Throughput Screening of Myxoid Liposarcoma Cell Lines: Survivin Is Essential for Tumor Growth |
| title_full_unstemmed | High-Throughput Screening of Myxoid Liposarcoma Cell Lines: Survivin Is Essential for Tumor Growth |
| title_short | High-Throughput Screening of Myxoid Liposarcoma Cell Lines: Survivin Is Essential for Tumor Growth |
| title_sort | high throughput screening of myxoid liposarcoma cell lines survivin is essential for tumor growth |
| url | http://www.sciencedirect.com/science/article/pii/S1936523317300803 |
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