Excess of NPM-ALK oncogenic signaling promotes cellular apoptosis and drug dependency
| Autor: | C Casati, Roberta Rigolio, Giovanni Giudici, Lydia Varesio, M E Boggio Merlo, Luca Mologni, Andrea D. Manazza, Roberto Chiarle, Silvia Bombelli, F Di Giacomo, Carlo Gambacorti-Passerini, Monica Ceccon, Mara Compagno, Claudia Voena, Matteo Menotti, Suzanne D. Turner, Chiara Ambrogio, Cristina Mastini, Teresa Poggio |
|---|---|
| Přispěvatelé: | Ceccon, M, Merlo, M, Mologni, L, Poggio, T, Varesio, L, Menotti, M, Bombelli, S, Rigolio, R, Manazza, A, Di Giacomo, F, Ambrogio, C, Giudici, G, Casati, C, Mastini, C, Compagno, M, Turner, S, GAMBACORTI PASSERINI, C, Chiarle, R, Voena, C, Turner, Suzanne [0000-0002-8439-4507], Apollo - University of Cambridge Repository |
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Cancer Research Oncogene Proteins Fusion Pyridines Apoptosis Mice SCID Histones 0302 clinical medicine Mice Inbred NOD hemic and lymphatic diseases Extracellular Signal-Regulated MAP Kinases Cells Cultured Mice Knockout Microscopy Confocal integumentary system Kinase Drug Synergism Cell cycle Protein-Tyrosine Kinases Hydrazines 030220 oncology & carcinogenesis Lymphoma Large-Cell Anaplastic RNA Interference Signal transduction Tyrosine kinase Nucleophosmin medicine.drug Signal Transduction Programmed cell death Cell Survival Blotting Western Transplantation Heterologous Biology Article 03 medical and health sciences Molecular Biology Genetics Crizotinib Cell Line Tumor medicine Animals Humans Kinase activity Protein Kinase Inhibitors Dose-Response Relationship Drug Triazoles 030104 developmental biology Cytoplasm Immunology Cancer research Pyrazoles |
| Zdroj: | Europe PubMed Central |
| Popis: | Most of the anaplastic large-cell lymphoma (ALCL) cases carry the t(2;5; p23;q35) that produces the fusion protein NPM-ALK (nucleophosmin-anaplastic lymphoma kinase). NPM-ALK-deregulated kinase activity drives several pathways that support malignant transformation of lymphoma cells. We found that in ALK-rearranged ALCL cell lines, NPM-ALK was distributed in equal amounts between the cytoplasm and the nucleus. Only the cytoplasmic portion was catalytically active in both cell lines and primary ALCL, whereas the nuclear portion was inactive because of heterodimerization with NPM1. Thus, about 50% of the NPM-ALK is not active and sequestered as NPM-ALK/NPM1 heterodimers in the nucleus. Overexpression or relocalization of NPM-ALK to the cytoplasm by NPM genetic knockout or knockdown caused ERK1/2 (extracellular signal-regulated protein kinases 1 and 2) increased phosphorylation and cell death through the engagement of an ATM/Chk2- and γH2AX (phosphorylated H2A histone family member X)-mediated DNA-damage response. Remarkably, human NPM-ALK-amplified cell lines resistant to ALK tyrosine kinase inhibitors (TKIs) underwent apoptosis upon drug withdrawal as a consequence of ERK1/2 hyperactivation. Altogether, these findings indicate that an excess of NPM-ALK activation and signaling induces apoptosis via oncogenic stress responses. A 'drug holiday' where the ALK TKI treatment is suspended could represent a therapeutic option in cells that become resistant by NPM-ALK amplification. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|