Abstract
The role and the mechanisms by which β1 integrins regulate the survival and chemoresistance of T cell acute lymphoblastic leukemia (T-ALL) still are poorly addressed. In this study, we demonstrate in T-ALL cell lines and primary blasts, that engagement of α2β1 integrin with its ligand collagen I (ColI), reduces doxorubicin-induced apoptosis, whereas fibronectin (Fn) had no effect. ColI but not Fn inhibited doxorubicin-induced mitochondrial depolarization, cytochrome c release, and activation of caspase-9 and -3. ColI but not Fn also prevented doxorubicin from down-regulating the levels of the prosurvival Bcl-2 protein family member Mcl-1. The effect of ColI on Mcl-1 occurred through the inhibition of doxorubicin-induced activation of c-Jun N-terminal kinase (JNK). Mcl-1 knockdown experiments showed that the maintenance of Mcl-1 levels is essential for ColI-mediated T-ALL cell survival. Furthermore, activation of MAPK/ERK, but not PI3K/AKT, is required for ColI-mediated inhibition of doxorubicin-induced JNK activation and apoptosis and for ColI-mediated maintenance of Mcl-1 levels. Thus, our study identifies α2β1 integrin as an important survival pathway in drug-induced apoptosis of T-ALL cells and suggests that its activation can contribute to the generation of drug resistance.
Publication types
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Clinical Trial
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Research Support, Non-U.S. Gov't
MeSH terms
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Antibiotics, Antineoplastic / pharmacology*
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Caspase 3 / genetics
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Caspase 3 / metabolism
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Caspase 9 / genetics
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Caspase 9 / metabolism
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Collagen Type I / genetics
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Collagen Type I / metabolism
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Cytochromes c / genetics
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Cytochromes c / metabolism
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Doxorubicin / pharmacology*
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Drug Resistance, Neoplasm*
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Enzyme Activation / genetics
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Extracellular Signal-Regulated MAP Kinases / genetics
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Extracellular Signal-Regulated MAP Kinases / metabolism*
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Female
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Fibronectins / genetics
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Fibronectins / metabolism
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Gene Knockdown Techniques
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Humans
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Integrin alpha2beta1 / genetics
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Integrin alpha2beta1 / metabolism*
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JNK Mitogen-Activated Protein Kinases / genetics
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JNK Mitogen-Activated Protein Kinases / metabolism
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Jurkat Cells
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MAP Kinase Signaling System / genetics
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Male
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Myeloid Cell Leukemia Sequence 1 Protein
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Phosphatidylinositol 3-Kinases / genetics
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Phosphatidylinositol 3-Kinases / metabolism
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / genetics
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / metabolism*
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / pathology
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / metabolism
Substances
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Antibiotics, Antineoplastic
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Collagen Type I
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Fibronectins
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Integrin alpha2beta1
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Myeloid Cell Leukemia Sequence 1 Protein
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Proto-Oncogene Proteins c-bcl-2
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Doxorubicin
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Cytochromes c
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Phosphatidylinositol 3-Kinases
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Proto-Oncogene Proteins c-akt
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Extracellular Signal-Regulated MAP Kinases
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JNK Mitogen-Activated Protein Kinases
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CASP3 protein, human
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Caspase 3
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Caspase 9