Overexpression of Tpl2 is linked to imatinib resistance and activation of MEK‐ERK and NF‐κB pathways in a model of chronic myeloid leukemia
| العنوان: | Overexpression of Tpl2 is linked to imatinib resistance and activation of MEK‐ERK and NF‐κB pathways in a model of chronic myeloid leukemia |
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| المؤلفون: | John Morgan, Karim Roder, Peng Zhang, Philip A. Gruppuso, Olin D Liang, Anna Chorzalska, Diana O. Treaba, Ting C. Zhao, John L. Reagan, Xiaoqing Yu, R. Shyama Prasad Rao, Steven Hines, Alexander Tepper, Nagib Ahsan, Patrycja M. Dubielecka, Adam J. Olszewski |
| المصدر: | Molecular Oncology, Vol 12, Iss 5, Pp 630-647 (2018) Molecular Oncology |
| بيانات النشر: | Wiley, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | 0301 basic medicine, MAPK/ERK pathway, Phosphopeptides, Proteomics, Cancer Research, Fusion Proteins, bcr-abl, IκB kinase, hemic and lymphatic diseases, Research Articles, COT1, Chemistry, MEK inhibitor, NF-kappa B, Myeloid leukemia, General Medicine, MAP Kinase Kinase Kinases, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 3. Good health, Dasatinib, src-Family Kinases, Oncology, Imatinib Mesylate, Molecular Medicine, Tyrosine kinase, medicine.drug, Research Article, Signal Transduction, MAP Kinase Signaling System, Models, Biological, lcsh:RC254-282, Bcr‐Abl1, 03 medical and health sciences, Tpl2, stem cells, Cell Line, Tumor, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Proto-Oncogene Proteins, Genetics, medicine, Animals, Humans, Mitogen-Activated Protein Kinase Kinases, Map3k8, Disease Models, Animal, 030104 developmental biology, Imatinib mesylate, Drug Resistance, Neoplasm, Cancer research, imatinib resistance, K562 cells |
| الوصف: | The introduction of tyrosine kinase inhibitors (TKI) has transformed chronic myeloid leukemia (CML) into a chronic disease with long‐term survival exceeding 85%. However, resistance of CML stem cells to TKI may contribute to the 50% relapse rate observed after TKI discontinuation in molecular remission. We previously described a model of resistance to imatinib mesylate (IM), in which K562 cells cultured in high concentrations of imatinib mesylate showed reduced Bcr‐Abl1 protein and activity levels while maintaining proliferative potential. Using quantitative phosphoproteomic analysis of these IM‐resistant cells, we have now identified significant upregulation of tumor progression locus (Tpl2), also known as cancer Osaka thyroid (COT1) kinase or Map3k8. Overexpression of Tpl2 in IM‐resistant cells was accompanied by elevated activities of Src family kinases (SFKs) and NF‐κB, MEK‐ERK signaling. CD34+ cells isolated from the bone marrow of patients with CML and exposed to IM in vitro showed increased MAP3K8 transcript levels. Dasatinib (SFK inhibitor), U0126 (MEK inhibitor), and PS‐1145 (IκB kinase (IKK) inhibitor) used in combination resulted in elimination of 65% of IM‐resistant cells and reduction in the colony‐forming capacity of CML CD34+ cells in methylcellulose assays by 80%. In addition, CML CD34+ cells cultured with the combination of inhibitors showed reduced MAP3K8 transcript levels. Overall, our data indicate that elevated Tpl2 protein and transcript levels are associated with resistance to IM and that combined inhibition of SFK, MEK, and NF‐κB signaling attenuates the survival of IM‐resistant CML cells and CML CD34+ cells. Therefore, combination of SFK, MEK, and NF‐κB inhibitors may offer a new therapeutic approach to overcome TKI resistance in CML patients. |
| اللغة: | English |
| تدمد: | 1574-7891 1878-0261 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::268eca283b59e476a4b5ff2744719991 https://doaj.org/article/61e7c5610dee4650acd0483ee9489b8a |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....268eca283b59e476a4b5ff2744719991 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15747891 18780261 |
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