NFκB signaling in alveolar rhabdomyosarcoma
| Autor: | Yuichi Ijiri, Denis C. Guttridge, Katherine J. Ladner, Brian P. Rubin, Matthew N. Svalina, Megan M. Cleary, Teagan P. Settelmeyer, Charles Keller, Atiya Mansoor |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
IKKβ Neuroscience (miscellaneous) lcsh:Medicine Medicine (miscellaneous) FOXO1 Mice SCID Biology General Biochemistry Genetics and Molecular Biology 03 medical and health sciences chemistry.chemical_compound Dogs Immunology and Microbiology (miscellaneous) Cell Line Tumor Rhabdomyosarcoma lcsh:Pathology medicine Animals Humans Rhabdomyosarcoma Alveolar Cancer Cell Proliferation Navitoclax Oncogene Cell growth Kinase lcsh:R Genetic Complementation Test NF-kappa B medicine.disease Allografts Fusion protein 3. Good health I-kappa B Kinase 030104 developmental biology Phenotype chemistry Proto-Oncogene Proteins c-bcl-2 Cell culture Alveolar rhabdomyosarcoma Cancer research Female Peptides Gene Deletion lcsh:RB1-214 Research Article NFκB Signal Transduction |
| Zdroj: | Disease Models & Mechanisms Disease Models & Mechanisms, Vol 10, Iss 9, Pp 1109-1115 (2017) |
| ISSN: | 1754-8411 1754-8403 |
| Popis: | 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. Summary: In a genetically engineered mouse model of aRMS, disrupting the NFκB pathway facilitated tumor initiation, suggesting it is a modifier of the disease rather than the driver. |
| Databáze: | OpenAIRE |
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