PAX3-FOXO1 Induces Up-Regulation of Noxa Sensitizing Alveolar Rhabdomyosarcoma Cells to Apoptosis
Alveolar rhabdomyosarcoma (ARMS) has a much poorer prognosis than the more common embryonal subtype. Most ARMS tumors characteristically possess a specific genomic translocation between the genes of PAX3/7 and FOXO1 (FKHR), which forms fusion proteins possessing the DNA binding domains of PAX3/7 and...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2013-07-01
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| Series: | Neoplasia: An International Journal for Oncology Research |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1476558613800681 |
| _version_ | 1819122576418406400 |
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| author | Amy D. Marshall Fabrizio Picchione Ramon I. Klein Geltink Gerard C. Grosveld |
| author_facet | Amy D. Marshall Fabrizio Picchione Ramon I. Klein Geltink Gerard C. Grosveld |
| author_sort | Amy D. Marshall |
| collection | DOAJ |
| description | Alveolar rhabdomyosarcoma (ARMS) has a much poorer prognosis than the more common embryonal subtype. Most ARMS tumors characteristically possess a specific genomic translocation between the genes of PAX3/7 and FOXO1 (FKHR), which forms fusion proteins possessing the DNA binding domains of PAX3/7 and the more transcriptionally potent transactivation domain of FOXO1. We have shown that the proapoptotic BH3-only family member Noxa is upregulated by the PAX3-FOXO1 fusion transcription factor in a p53-independent manner. The increased expression of Noxa renders PAX3-FOXO1-expressing cells more susceptible to apoptosis induced by a ă-secretase inhibitor (GSI1, Z-LLNle-CHO), the proteasome inhibitor bortezomib, and BH3 mimetic ABT-737. Apoptosis in response to bortezomib can be overcome by shRNA knockdown of Noxa. In vivo treatment with bortezomib reduced the growth of tumors derived from a PAX3-FOXO1-expressing primary myoblast tumor model and RH41 xenografts. We therefore demonstrate that PAX3-FOXO1 up-regulation of Noxa represents an unanticipated aspect of ARMS tumor biology that creates a therapeutic window to allow induction of apoptosis in ARMS cells. |
| first_indexed | 2024-12-22T06:54:39Z |
| format | Article |
| id | doaj.art-9338948efdc8457ca861b52738b52f93 |
| institution | Directory Open Access Journal |
| issn | 1476-5586 1522-8002 |
| language | English |
| last_indexed | 2024-12-22T06:54:39Z |
| publishDate | 2013-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neoplasia: An International Journal for Oncology Research |
| spelling | doaj.art-9338948efdc8457ca861b52738b52f932022-12-21T18:35:00ZengElsevierNeoplasia: An International Journal for Oncology Research1476-55861522-80022013-07-0115773874810.1593/neo.121888PAX3-FOXO1 Induces Up-Regulation of Noxa Sensitizing Alveolar Rhabdomyosarcoma Cells to ApoptosisAmy D. Marshall0Fabrizio Picchione1Ramon I. Klein Geltink2Gerard C. Grosveld3Department of Genetics, St Jude Children's Research Hospital, Memphis, TNDepartment of Genetics, St Jude Children's Research Hospital, Memphis, TNDepartment of Genetics, St Jude Children's Research Hospital, Memphis, TNDepartment of Genetics, St Jude Children's Research Hospital, Memphis, TNAlveolar rhabdomyosarcoma (ARMS) has a much poorer prognosis than the more common embryonal subtype. Most ARMS tumors characteristically possess a specific genomic translocation between the genes of PAX3/7 and FOXO1 (FKHR), which forms fusion proteins possessing the DNA binding domains of PAX3/7 and the more transcriptionally potent transactivation domain of FOXO1. We have shown that the proapoptotic BH3-only family member Noxa is upregulated by the PAX3-FOXO1 fusion transcription factor in a p53-independent manner. The increased expression of Noxa renders PAX3-FOXO1-expressing cells more susceptible to apoptosis induced by a ă-secretase inhibitor (GSI1, Z-LLNle-CHO), the proteasome inhibitor bortezomib, and BH3 mimetic ABT-737. Apoptosis in response to bortezomib can be overcome by shRNA knockdown of Noxa. In vivo treatment with bortezomib reduced the growth of tumors derived from a PAX3-FOXO1-expressing primary myoblast tumor model and RH41 xenografts. We therefore demonstrate that PAX3-FOXO1 up-regulation of Noxa represents an unanticipated aspect of ARMS tumor biology that creates a therapeutic window to allow induction of apoptosis in ARMS cells.http://www.sciencedirect.com/science/article/pii/S1476558613800681 |
| spellingShingle | Amy D. Marshall Fabrizio Picchione Ramon I. Klein Geltink Gerard C. Grosveld PAX3-FOXO1 Induces Up-Regulation of Noxa Sensitizing Alveolar Rhabdomyosarcoma Cells to Apoptosis Neoplasia: An International Journal for Oncology Research |
| title | PAX3-FOXO1 Induces Up-Regulation of Noxa Sensitizing Alveolar Rhabdomyosarcoma Cells to Apoptosis |
| title_full | PAX3-FOXO1 Induces Up-Regulation of Noxa Sensitizing Alveolar Rhabdomyosarcoma Cells to Apoptosis |
| title_fullStr | PAX3-FOXO1 Induces Up-Regulation of Noxa Sensitizing Alveolar Rhabdomyosarcoma Cells to Apoptosis |
| title_full_unstemmed | PAX3-FOXO1 Induces Up-Regulation of Noxa Sensitizing Alveolar Rhabdomyosarcoma Cells to Apoptosis |
| title_short | PAX3-FOXO1 Induces Up-Regulation of Noxa Sensitizing Alveolar Rhabdomyosarcoma Cells to Apoptosis |
| title_sort | pax3 foxo1 induces up regulation of noxa sensitizing alveolar rhabdomyosarcoma cells to apoptosis |
| url | http://www.sciencedirect.com/science/article/pii/S1476558613800681 |
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