The survivin/XIAP suppressant YM155 impairs clonal growth and induces apoptosis in JAK2V617F cells
The central role of the control of apoptosis in the pathophysiology of Philadelphia chromosome-negative myeloproliferative neoplasms has recently been reinforced in genetic and pharmacological studies. The inhibitor of apoptosis protein family has eight members and plays an important role in apoptos...
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Elsevier
2024-12-01
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| Series: | Hematology, Transfusion and Cell Therapy |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2531137924003092 |
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| author | Jorge Antonio Elias Godoy Carlos Keli Lima Eduardo Magalhães Rego Leticia Veras Costa-Lotufo João Agostinho Machado-Neto |
| author_facet | Jorge Antonio Elias Godoy Carlos Keli Lima Eduardo Magalhães Rego Leticia Veras Costa-Lotufo João Agostinho Machado-Neto |
| author_sort | Jorge Antonio Elias Godoy Carlos |
| collection | DOAJ |
| description | The central role of the control of apoptosis in the pathophysiology of Philadelphia chromosome-negative myeloproliferative neoplasms has recently been reinforced in genetic and pharmacological studies. The inhibitor of apoptosis protein family has eight members and plays an important role in apoptosis, with the most studied being survivin (BIRC5) and X-linked inhibitor of apoptosis (XIAP). YM155 is a small molecule with antineoplastic potential that has been described as a suppressant of survivin and XIAP. In the present study, BIRC5 expression was significantly increased in primary myelofibrosis patients compared to healthy donors. On the other hand, XIAP expression was reduced in myeloproliferative neoplasms patients. In JAK2V617F cells, YM155 reduces cell viability and autonomous clonal growth and induces apoptosis, cell cycle arrest, and autophagy. HEL cells that show greater malignancy are more sensitive to the drug than SET2 cells. In the molecular scenario, YM155 modulates apoptosis-, cell cycle-, DNA damage- and autophagy-related genes. Protein expression analysis corroborates the observed cellular phenotype and exploratory gene expression findings. In summary, our results indicate that survivin/BIRC5 and XIAP are differently expressed in myeloproliferative neoplasms and YM155 has multiple antineoplastic effects on JAK2V617F cells suggesting that inhibitor of apoptosis proteins may be a target for pharmacological interventions in the treatment of these diseases. |
| format | Article |
| id | doaj-art-db6927c88e534f198576c1dbfa2ffccd |
| institution | Kabale University |
| issn | 2531-1379 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Hematology, Transfusion and Cell Therapy |
| spelling | doaj-art-db6927c88e534f198576c1dbfa2ffccd2024-12-21T04:29:37ZengElsevierHematology, Transfusion and Cell Therapy2531-13792024-12-0146S217S227The survivin/XIAP suppressant YM155 impairs clonal growth and induces apoptosis in JAK2V617F cellsJorge Antonio Elias Godoy Carlos0Keli Lima1Eduardo Magalhães Rego2Leticia Veras Costa-Lotufo3João Agostinho Machado-Neto4Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, BrazilDepartment of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil; Laboratory of Medical Investigation in Pathogenesis and Targeted Therapy in Onco-Immuno-Hematology (LIM-31), Department of Internal Medicine, Hematology Division, Medical School, University of São Paulo, São Paulo, BrazilLaboratory of Medical Investigation in Pathogenesis and Targeted Therapy in Onco-Immuno-Hematology (LIM-31), Department of Internal Medicine, Hematology Division, Medical School, University of São Paulo, São Paulo, BrazilDepartment of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, BrazilDepartment of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil; Corresponding author at: Department of Pharmacology, Institute of Biomedical Sciences of University of São Paulo, Av. Prof. Lineu Prestes, 1524, CEP: 05508-900, São Paulo, SP, Brazil.The central role of the control of apoptosis in the pathophysiology of Philadelphia chromosome-negative myeloproliferative neoplasms has recently been reinforced in genetic and pharmacological studies. The inhibitor of apoptosis protein family has eight members and plays an important role in apoptosis, with the most studied being survivin (BIRC5) and X-linked inhibitor of apoptosis (XIAP). YM155 is a small molecule with antineoplastic potential that has been described as a suppressant of survivin and XIAP. In the present study, BIRC5 expression was significantly increased in primary myelofibrosis patients compared to healthy donors. On the other hand, XIAP expression was reduced in myeloproliferative neoplasms patients. In JAK2V617F cells, YM155 reduces cell viability and autonomous clonal growth and induces apoptosis, cell cycle arrest, and autophagy. HEL cells that show greater malignancy are more sensitive to the drug than SET2 cells. In the molecular scenario, YM155 modulates apoptosis-, cell cycle-, DNA damage- and autophagy-related genes. Protein expression analysis corroborates the observed cellular phenotype and exploratory gene expression findings. In summary, our results indicate that survivin/BIRC5 and XIAP are differently expressed in myeloproliferative neoplasms and YM155 has multiple antineoplastic effects on JAK2V617F cells suggesting that inhibitor of apoptosis proteins may be a target for pharmacological interventions in the treatment of these diseases.http://www.sciencedirect.com/science/article/pii/S2531137924003092Myeloproliferative neoplasmsInhibitor of apoptosis proteinsSurvivingXIAPYM155 |
| spellingShingle | Jorge Antonio Elias Godoy Carlos Keli Lima Eduardo Magalhães Rego Leticia Veras Costa-Lotufo João Agostinho Machado-Neto The survivin/XIAP suppressant YM155 impairs clonal growth and induces apoptosis in JAK2V617F cells Hematology, Transfusion and Cell Therapy Myeloproliferative neoplasms Inhibitor of apoptosis proteins Surviving XIAP YM155 |
| title | The survivin/XIAP suppressant YM155 impairs clonal growth and induces apoptosis in JAK2V617F cells |
| title_full | The survivin/XIAP suppressant YM155 impairs clonal growth and induces apoptosis in JAK2V617F cells |
| title_fullStr | The survivin/XIAP suppressant YM155 impairs clonal growth and induces apoptosis in JAK2V617F cells |
| title_full_unstemmed | The survivin/XIAP suppressant YM155 impairs clonal growth and induces apoptosis in JAK2V617F cells |
| title_short | The survivin/XIAP suppressant YM155 impairs clonal growth and induces apoptosis in JAK2V617F cells |
| title_sort | survivin xiap suppressant ym155 impairs clonal growth and induces apoptosis in jak2v617f cells |
| topic | Myeloproliferative neoplasms Inhibitor of apoptosis proteins Surviving XIAP YM155 |
| url | http://www.sciencedirect.com/science/article/pii/S2531137924003092 |
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