BCL-2 phosphorylation modulates sensitivity to the BH3 mimetic GX15-070 (Obatoclax) and reduces its synergistic interaction with bortezomib in chronic lymphocytic leukemia cells
| العنوان: | BCL-2 phosphorylation modulates sensitivity to the BH3 mimetic GX15-070 (Obatoclax) and reduces its synergistic interaction with bortezomib in chronic lymphocytic leukemia cells |
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| المؤلفون: | Mai Nguyen, Gordon C. Shore, Gaël Roué, Dolors Colomer, Elias Campo, Patricia Pérez-Galán, Mónica López-Guerra, Emili Montserrat, Neus Villamor |
| المصدر: | Leukemia. 22:1712-1720 |
| بيانات النشر: | Springer Science and Business Media LLC, 2008. |
| سنة النشر: | 2008 |
| مصطلحات موضوعية: | MAPK/ERK pathway, Cancer Research, Indoles, Chronic lymphocytic leukemia, Apoptosis, Lymphoma, Mantle-Cell, Biology, Bortezomib, chemistry.chemical_compound, hemic and lymphatic diseases, Antineoplastic Combined Chemotherapy Protocols, Tumor Cells, Cultured, medicine, Humans, Protease Inhibitors, Pyrroles, Phosphorylation, Kinase, Drug Synergism, Hematology, medicine.disease, Boronic Acids, Leukemia, Lymphocytic, Chronic, B-Cell, Mitochondria, Proto-Oncogene Proteins c-bcl-2, Oncology, Proteasome, chemistry, Pyrazines, Cancer research, Proteasome inhibitor, medicine.drug, Obatoclax |
| الوصف: | Chronic lymphocytic leukemia (CLL) is a B-cell lymphoid neoplasm with deregulated apoptosis and overexpression of several antiapoptotic BCL-2 proteins. GX15-070/Obatoclax is a small-molecule BH3 mimetic compound that has shown activity against several hematologic malignancies and solid tumors. In the present work, we report that GX15-070 led to the disruption of BCL-2/BIM and MCL-1/BAK complexes in CLL cells, followed by the activation of the mitochondrial apoptotic pathway. CLL cells showed lower sensitivity to GX15-070 than primary mantle cell lymphoma (MCL) ones, in correlation with higher levels of phosphorylated BCL-2 at serine 70 residue (pBCL-2(Ser70)) in CLL cells. Decrease in BCL-2 phosphorylation by extracellular signal-regulated kinase (ERK)1/2 inhibition increased CLL sensitivity to GX15-070, while blocking BCL-2 dephosphorylation using a PP2A antagonist reduced the activity of this BH3 mimetic. GX15-070 activity was increased by cotreatment with the proteasome inhibitor bortezomib. However, as proteasome inhibition led to the accumulation of phosphorylated BCL-2, the degree of interaction between GX15-070 and bortezomib was regulated by basal pBCL-2(Ser70) levels. These results support the role of BCL-2 phosphorylation as a mechanism of resistance to BH3 mimetic compounds, and demonstrate that combination approaches including ERK inhibitors could enhance BH3 mimetics activity both alone or in combination with proteasome inhibitors. |
| تدمد: | 1476-5551 0887-6924 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::9251ea26f2dd4c94eacb73800d436022Test https://doi.org/10.1038/leu.2008.175Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....9251ea26f2dd4c94eacb73800d436022 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14765551 08876924 |
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