NFκB signaling in alveolar rhabdomyosarcoma
Alveolar rhabdomyosarcoma (aRMS) is a pediatric soft tissue cancer commonly associated with a chromosomal translocation that leads to the expression of a Pax3:Foxo1 or Pax7:Foxo1 fusion protein, the developmental underpinnings of which may give clues to its therapeutic approaches. In aRMS, the NFκB–...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
The Company of Biologists
2017-09-01
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| Series: | Disease Models & Mechanisms |
| Subjects: | |
| Online Access: | http://dmm.biologists.org/content/10/9/1109 |
| _version_ | 1819076850605883392 |
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| author | Megan M. Cleary Atiya Mansoor Teagan Settelmeyer Yuichi Ijiri Katherine J. Ladner Matthew N. Svalina Brian P. Rubin Denis C. Guttridge Charles Keller |
| author_facet | Megan M. Cleary Atiya Mansoor Teagan Settelmeyer Yuichi Ijiri Katherine J. Ladner Matthew N. Svalina Brian P. Rubin Denis C. Guttridge Charles Keller |
| author_sort | Megan M. Cleary |
| collection | DOAJ |
| description | Alveolar rhabdomyosarcoma (aRMS) is a pediatric soft tissue cancer commonly associated with a chromosomal translocation that leads to the expression of a Pax3:Foxo1 or Pax7:Foxo1 fusion protein, the developmental underpinnings of which may give clues to its therapeutic approaches. In aRMS, the NFκB–YY1–miR-29 regulatory circuit is dysregulated, resulting in repression of miR-29 and loss of the associated tumor suppressor activity. To further elucidate the role of NFκB in aRMS, we first tested 55 unique sarcoma cell lines and primary cell cultures in a large-scale chemical screen targeting diverse molecular pathways. We found that pharmacological inhibition of NFκB activity resulted in decreased cell proliferation of many of the aRMS tumor cultures. Surprisingly, mice that were orthotopically allografted with aRMS tumor cells exhibited no difference in tumor growth when administered an NFκB inhibitor, compared to control. Furthermore, inhibition of NFκB by genetically ablating its activating kinase inhibitor, IKKβ, by conditional deletion in a mouse model harboring the Pax3:Foxo1 chimeric oncogene failed to abrogate spontaneous tumor growth. Genetically engineered mice with conditionally deleted IKKβ exhibited a paradoxical decrease in tumor latency compared with those with active NFκB. However, using a synthetic-lethal approach, primary cell cultures derived from tumors with inactivated NFκB showed sensitivity to the BCL-2 inhibitor navitoclax. When used in combination with an NFκB inhibitor, navitoclax was synergistic in decreasing the growth of both human and IKKβ wild-type mouse aRMS cells, indicating that inactivation of NFκB alone may not be sufficient for reducing tumor growth, but, when combined with another targeted therapeutic, may be clinically beneficial. |
| first_indexed | 2024-12-21T18:47:51Z |
| format | Article |
| id | doaj.art-482fff5d3d17486dbea30258167b2d1d |
| institution | Directory Open Access Journal |
| issn | 1754-8403 1754-8411 |
| language | English |
| last_indexed | 2024-12-21T18:47:51Z |
| publishDate | 2017-09-01 |
| publisher | The Company of Biologists |
| record_format | Article |
| series | Disease Models & Mechanisms |
| spelling | doaj.art-482fff5d3d17486dbea30258167b2d1d2022-12-21T18:53:49ZengThe Company of BiologistsDisease Models & Mechanisms1754-84031754-84112017-09-011091109111510.1242/dmm.030882030882NFκB signaling in alveolar rhabdomyosarcomaMegan M. Cleary0Atiya Mansoor1Teagan Settelmeyer2Yuichi Ijiri3Katherine J. Ladner4Matthew N. Svalina5Brian P. Rubin6Denis C. Guttridge7Charles Keller8 Children's Cancer Therapy Development Institute, Beaverton, OR 97005, USA Department of Pathology, Oregon Health and Science University, Portland, OR 97239, USA Children's Cancer Therapy Development Institute, Beaverton, OR 97005, USA Department of Cancer Biology and Genetics and The Arthur G. James Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, OH 43210, USA Department of Cancer Biology and Genetics and The Arthur G. James Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, OH 43210, USA Children's Cancer Therapy Development Institute, Beaverton, OR 97005, USA Department of Anatomic Pathology, Department of Molecular Genetics, Taussig Cancer Center, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA Department of Cancer Biology and Genetics and The Arthur G. James Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, OH 43210, USA Children's Cancer Therapy Development Institute, Beaverton, OR 97005, USA Alveolar rhabdomyosarcoma (aRMS) is a pediatric soft tissue cancer commonly associated with a chromosomal translocation that leads to the expression of a Pax3:Foxo1 or Pax7:Foxo1 fusion protein, the developmental underpinnings of which may give clues to its therapeutic approaches. In aRMS, the NFκB–YY1–miR-29 regulatory circuit is dysregulated, resulting in repression of miR-29 and loss of the associated tumor suppressor activity. To further elucidate the role of NFκB in aRMS, we first tested 55 unique sarcoma cell lines and primary cell cultures in a large-scale chemical screen targeting diverse molecular pathways. We found that pharmacological inhibition of NFκB activity resulted in decreased cell proliferation of many of the aRMS tumor cultures. Surprisingly, mice that were orthotopically allografted with aRMS tumor cells exhibited no difference in tumor growth when administered an NFκB inhibitor, compared to control. Furthermore, inhibition of NFκB by genetically ablating its activating kinase inhibitor, IKKβ, by conditional deletion in a mouse model harboring the Pax3:Foxo1 chimeric oncogene failed to abrogate spontaneous tumor growth. Genetically engineered mice with conditionally deleted IKKβ exhibited a paradoxical decrease in tumor latency compared with those with active NFκB. However, using a synthetic-lethal approach, primary cell cultures derived from tumors with inactivated NFκB showed sensitivity to the BCL-2 inhibitor navitoclax. When used in combination with an NFκB inhibitor, navitoclax was synergistic in decreasing the growth of both human and IKKβ wild-type mouse aRMS cells, indicating that inactivation of NFκB alone may not be sufficient for reducing tumor growth, but, when combined with another targeted therapeutic, may be clinically beneficial.http://dmm.biologists.org/content/10/9/1109RhabdomyosarcomaNFκBIKKβCancer |
| spellingShingle | Megan M. Cleary Atiya Mansoor Teagan Settelmeyer Yuichi Ijiri Katherine J. Ladner Matthew N. Svalina Brian P. Rubin Denis C. Guttridge Charles Keller NFκB signaling in alveolar rhabdomyosarcoma Disease Models & Mechanisms Rhabdomyosarcoma NFκB IKKβ Cancer |
| title | NFκB signaling in alveolar rhabdomyosarcoma |
| title_full | NFκB signaling in alveolar rhabdomyosarcoma |
| title_fullStr | NFκB signaling in alveolar rhabdomyosarcoma |
| title_full_unstemmed | NFκB signaling in alveolar rhabdomyosarcoma |
| title_short | NFκB signaling in alveolar rhabdomyosarcoma |
| title_sort | nfκb signaling in alveolar rhabdomyosarcoma |
| topic | Rhabdomyosarcoma NFκB IKKβ Cancer |
| url | http://dmm.biologists.org/content/10/9/1109 |
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