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 |
|---|---|
| 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 |
| ResultId |
1 |
|---|---|
| Header |
edsair OpenAIRE edsair.doi.dedup.....9251ea26f2dd4c94eacb73800d436022 791 3 unknown 790.744323730469 |
| PLink |
https://search.ebscohost.com/login.aspx?direct=true&site=eds-live&scope=site&db=edsair&AN=edsair.doi.dedup.....9251ea26f2dd4c94eacb73800d436022&custid=s6537998&authtype=sso |
| FullText |
Array
(
[Availability] => 0
)
|
| Items |
Array
(
[Name] => Title
[Label] => Title
[Group] => Ti
[Data] => BCL-2 phosphorylation modulates sensitivity to the BH3 mimetic GX15-070 (Obatoclax) and reduces its synergistic interaction with bortezomib in chronic lymphocytic leukemia cells
)
Array ( [Name] => Author [Label] => Authors [Group] => Au [Data] => <searchLink fieldCode="AR" term="%22Mai+Nguyen%22">Mai Nguyen</searchLink><br /><searchLink fieldCode="AR" term="%22Gordon+C%2E+Shore%22">Gordon C. Shore</searchLink><br /><searchLink fieldCode="AR" term="%22Gaël+Roué%22">Gaël Roué</searchLink><br /><searchLink fieldCode="AR" term="%22Dolors+Colomer%22">Dolors Colomer</searchLink><br /><searchLink fieldCode="AR" term="%22Elias+Campo%22">Elias Campo</searchLink><br /><searchLink fieldCode="AR" term="%22Patricia+Pérez-Galán%22">Patricia Pérez-Galán</searchLink><br /><searchLink fieldCode="AR" term="%22Mónica+López-Guerra%22">Mónica López-Guerra</searchLink><br /><searchLink fieldCode="AR" term="%22Emili+Montserrat%22">Emili Montserrat</searchLink><br /><searchLink fieldCode="AR" term="%22Neus+Villamor%22">Neus Villamor</searchLink> ) Array ( [Name] => TitleSource [Label] => Source [Group] => Src [Data] => <i>Leukemia</i>. 22:1712-1720 ) Array ( [Name] => Publisher [Label] => Publisher Information [Group] => PubInfo [Data] => Springer Science and Business Media LLC, 2008. ) Array ( [Name] => DatePubCY [Label] => Publication Year [Group] => Date [Data] => 2008 ) Array ( [Name] => Subject [Label] => Subject Terms [Group] => Su [Data] => <searchLink fieldCode="DE" term="%22MAPK%2FERK+pathway%22">MAPK/ERK pathway</searchLink><br /><searchLink fieldCode="DE" term="%22Cancer+Research%22">Cancer Research</searchLink><br /><searchLink fieldCode="DE" term="%22Indoles%22">Indoles</searchLink><br /><searchLink fieldCode="DE" term="%22Chronic+lymphocytic+leukemia%22">Chronic lymphocytic leukemia</searchLink><br /><searchLink fieldCode="DE" term="%22Apoptosis%22">Apoptosis</searchLink><br /><searchLink fieldCode="DE" term="%22Lymphoma%2C+Mantle-Cell%22">Lymphoma, Mantle-Cell</searchLink><br /><searchLink fieldCode="DE" term="%22Biology%22">Biology</searchLink><br /><searchLink fieldCode="DE" term="%22Bortezomib%22">Bortezomib</searchLink><br /><searchLink fieldCode="DE" term="%22chemistry%2Echemical%5Fcompound%22">chemistry.chemical_compound</searchLink><br /><searchLink fieldCode="DE" term="%22hemic+and+lymphatic+diseases%22">hemic and lymphatic diseases</searchLink><br /><searchLink fieldCode="DE" term="%22Antineoplastic+Combined+Chemotherapy+Protocols%22">Antineoplastic Combined Chemotherapy Protocols</searchLink><br /><searchLink fieldCode="DE" term="%22Tumor+Cells%2C+Cultured%22">Tumor Cells, Cultured</searchLink><br /><searchLink fieldCode="DE" term="%22medicine%22">medicine</searchLink><br /><searchLink fieldCode="DE" term="%22Humans%22">Humans</searchLink><br /><searchLink fieldCode="DE" term="%22Protease+Inhibitors%22">Protease Inhibitors</searchLink><br /><searchLink fieldCode="DE" term="%22Pyrroles%22">Pyrroles</searchLink><br /><searchLink fieldCode="DE" term="%22Phosphorylation%22">Phosphorylation</searchLink><br /><searchLink fieldCode="DE" term="%22Kinase%22">Kinase</searchLink><br /><searchLink fieldCode="DE" term="%22Drug+Synergism%22">Drug Synergism</searchLink><br /><searchLink fieldCode="DE" term="%22Hematology%22">Hematology</searchLink><br /><searchLink fieldCode="DE" term="%22medicine%2Edisease%22">medicine.disease</searchLink><br /><searchLink fieldCode="DE" term="%22Boronic+Acids%22">Boronic Acids</searchLink><br /><searchLink fieldCode="DE" term="%22Leukemia%2C+Lymphocytic%2C+Chronic%2C+B-Cell%22">Leukemia, Lymphocytic, Chronic, B-Cell</searchLink><br /><searchLink fieldCode="DE" term="%22Mitochondria%22">Mitochondria</searchLink><br /><searchLink fieldCode="DE" term="%22Proto-Oncogene+Proteins+c-bcl-2%22">Proto-Oncogene Proteins c-bcl-2</searchLink><br /><searchLink fieldCode="DE" term="%22Oncology%22">Oncology</searchLink><br /><searchLink fieldCode="DE" term="%22Proteasome%22">Proteasome</searchLink><br /><searchLink fieldCode="DE" term="%22chemistry%22">chemistry</searchLink><br /><searchLink fieldCode="DE" term="%22Pyrazines%22">Pyrazines</searchLink><br /><searchLink fieldCode="DE" term="%22Cancer+research%22">Cancer research</searchLink><br /><searchLink fieldCode="DE" term="%22Proteasome+inhibitor%22">Proteasome inhibitor</searchLink><br /><searchLink fieldCode="DE" term="%22medicine%2Edrug%22">medicine.drug</searchLink><br /><searchLink fieldCode="DE" term="%22Obatoclax%22">Obatoclax</searchLink> ) Array ( [Name] => Abstract [Label] => Description [Group] => Ab [Data] => 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. ) Array ( [Name] => ISSN [Label] => ISSN [Group] => ISSN [Data] => 1476-5551<br />0887-6924 ) Array ( [Name] => URL [Label] => Access URL [Group] => URL [Data] => <link linkTarget="URL" linkTerm="https://explore.openaire.eu/search/publication?articleId=doi_dedup___::9251ea26f2dd4c94eacb73800d436022" linkWindow="_blank">https://explore.openaire.eu/search/publication?articleId=doi_dedup___::9251ea26f2dd4c94eacb73800d436022</link><br /><link linkTarget="URL" linkTerm="https://doi.org/10.1038/leu.2008.175" linkWindow="_blank">https://doi.org/10.1038/leu.2008.175</link> ) Array ( [Name] => Copyright [Label] => Rights [Group] => Cpyrght [Data] => OPEN ) Array ( [Name] => AN [Label] => Accession Number [Group] => ID [Data] => edsair.doi.dedup.....9251ea26f2dd4c94eacb73800d436022 ) |
| RecordInfo |
Array
(
[BibEntity] => Array
(
[Languages] => Array
(
[0] => Array
(
[Text] => Undetermined
)
)
[PhysicalDescription] => Array
(
[Pagination] => Array
(
[PageCount] => 9
[StartPage] => 1712
)
)
[Subjects] => Array
(
[0] => Array
(
[SubjectFull] => MAPK/ERK pathway
[Type] => general
)
[1] => Array
(
[SubjectFull] => Cancer Research
[Type] => general
)
[2] => Array
(
[SubjectFull] => Indoles
[Type] => general
)
[3] => Array
(
[SubjectFull] => Chronic lymphocytic leukemia
[Type] => general
)
[4] => Array
(
[SubjectFull] => Apoptosis
[Type] => general
)
[5] => Array
(
[SubjectFull] => Lymphoma, Mantle-Cell
[Type] => general
)
[6] => Array
(
[SubjectFull] => Biology
[Type] => general
)
[7] => Array
(
[SubjectFull] => Bortezomib
[Type] => general
)
[8] => Array
(
[SubjectFull] => chemistry.chemical_compound
[Type] => general
)
[9] => Array
(
[SubjectFull] => hemic and lymphatic diseases
[Type] => general
)
[10] => Array
(
[SubjectFull] => Antineoplastic Combined Chemotherapy Protocols
[Type] => general
)
[11] => Array
(
[SubjectFull] => Tumor Cells, Cultured
[Type] => general
)
[12] => Array
(
[SubjectFull] => medicine
[Type] => general
)
[13] => Array
(
[SubjectFull] => Humans
[Type] => general
)
[14] => Array
(
[SubjectFull] => Protease Inhibitors
[Type] => general
)
[15] => Array
(
[SubjectFull] => Pyrroles
[Type] => general
)
[16] => Array
(
[SubjectFull] => Phosphorylation
[Type] => general
)
[17] => Array
(
[SubjectFull] => Kinase
[Type] => general
)
[18] => Array
(
[SubjectFull] => Drug Synergism
[Type] => general
)
[19] => Array
(
[SubjectFull] => Hematology
[Type] => general
)
[20] => Array
(
[SubjectFull] => medicine.disease
[Type] => general
)
[21] => Array
(
[SubjectFull] => Boronic Acids
[Type] => general
)
[22] => Array
(
[SubjectFull] => Leukemia, Lymphocytic, Chronic, B-Cell
[Type] => general
)
[23] => Array
(
[SubjectFull] => Mitochondria
[Type] => general
)
[24] => Array
(
[SubjectFull] => Proto-Oncogene Proteins c-bcl-2
[Type] => general
)
[25] => Array
(
[SubjectFull] => Oncology
[Type] => general
)
[26] => Array
(
[SubjectFull] => Proteasome
[Type] => general
)
[27] => Array
(
[SubjectFull] => chemistry
[Type] => general
)
[28] => Array
(
[SubjectFull] => Pyrazines
[Type] => general
)
[29] => Array
(
[SubjectFull] => Cancer research
[Type] => general
)
[30] => Array
(
[SubjectFull] => Proteasome inhibitor
[Type] => general
)
[31] => Array
(
[SubjectFull] => medicine.drug
[Type] => general
)
[32] => Array
(
[SubjectFull] => Obatoclax
[Type] => general
)
)
[Titles] => Array
(
[0] => Array
(
[TitleFull] => BCL-2 phosphorylation modulates sensitivity to the BH3 mimetic GX15-070 (Obatoclax) and reduces its synergistic interaction with bortezomib in chronic lymphocytic leukemia cells
[Type] => main
)
)
)
[BibRelationships] => Array
(
[HasContributorRelationships] => Array
(
[0] => Array
(
[PersonEntity] => Array
(
[Name] => Array
(
[NameFull] => Mai Nguyen
)
)
)
[1] => Array
(
[PersonEntity] => Array
(
[Name] => Array
(
[NameFull] => Gordon C. Shore
)
)
)
[2] => Array
(
[PersonEntity] => Array
(
[Name] => Array
(
[NameFull] => Gaël Roué
)
)
)
[3] => Array
(
[PersonEntity] => Array
(
[Name] => Array
(
[NameFull] => Dolors Colomer
)
)
)
[4] => Array
(
[PersonEntity] => Array
(
[Name] => Array
(
[NameFull] => Elias Campo
)
)
)
[5] => Array
(
[PersonEntity] => Array
(
[Name] => Array
(
[NameFull] => Patricia Pérez-Galán
)
)
)
[6] => Array
(
[PersonEntity] => Array
(
[Name] => Array
(
[NameFull] => Mónica López-Guerra
)
)
)
[7] => Array
(
[PersonEntity] => Array
(
[Name] => Array
(
[NameFull] => Emili Montserrat
)
)
)
[8] => Array
(
[PersonEntity] => Array
(
[Name] => Array
(
[NameFull] => Neus Villamor
)
)
)
)
[IsPartOfRelationships] => Array
(
[0] => Array
(
[BibEntity] => Array
(
[Dates] => Array
(
[0] => Array
(
[D] => 03
[M] => 07
[Type] => published
[Y] => 2008
)
)
[Identifiers] => Array
(
[0] => Array
(
[Type] => issn-print
[Value] => 14765551
)
[1] => Array
(
[Type] => issn-print
[Value] => 08876924
)
[2] => Array
(
[Type] => issn-locals
[Value] => edsair
)
[3] => Array
(
[Type] => issn-locals
[Value] => edsairFT
)
)
[Numbering] => Array
(
[0] => Array
(
[Type] => volume
[Value] => 22
)
)
[Titles] => Array
(
[0] => Array
(
[TitleFull] => Leukemia
[Type] => main
)
)
)
)
)
)
)
|
| IllustrationInfo |