Abstract
Growing evidence indicates that cell adhesion to extracellular matrix (ECM) plays an important role in cancer chemoresistance. Leukemic T cells express several adhesion receptors of the β1 integrin subfamily with which they interact with ECM. However, the role of β1 integrins in chemoresistance of T-cell acute lymphoblastic leukemia (T-ALL) is still ill defined. In this study, we demonstrate that interactions of human T-ALL cell lines and primary blasts with three-dimensional matrices including Matrigel and collagen type I gel promote their resistance to doxorubicin via β1 integrin. The blockade of β1 integrin with a specific neutralizing antibody sensitized xenografted CEM leukemic cells to doxorubicin, diminished the leukemic burden in the bone marrow and resulted in the extension of animal survival. Mechanistically, Matrigel/β1 integrin interaction enhanced T-ALL chemoresistance by promoting doxorubicin efflux through the activation of the ABCC1 drug transporter. Finally, our findings showed that Matrigel/β1 interaction enhanced doxorubicin efflux and chemoresistance by activating the FAK-related proline-rich tyrosine kinase 2 (PYK2) as both PYK2 inhibitor and siRNA diminished the effect of Matrigel. Collectively, these results support the role of β1 integrin in T-ALL chemoresistance and suggest that the β1 integrin pathway can constitute a therapeutic target to avoid chemoresistance and relapsed-disease in human T-ALL.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibiotics, Antineoplastic / pharmacology*
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Antibodies, Neutralizing / pharmacology
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Apoptosis / drug effects
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Cell Adhesion / drug effects
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Cell Line, Tumor
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Collagen / chemistry
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Collagen / metabolism
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Collagen Type I / chemistry
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Collagen Type I / metabolism
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Doxorubicin / pharmacology*
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Drug Combinations
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Drug Resistance, Neoplasm / genetics
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Extracellular Matrix / chemistry
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Extracellular Matrix / metabolism
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Focal Adhesion Kinase 2 / antagonists & inhibitors
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Focal Adhesion Kinase 2 / genetics*
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Focal Adhesion Kinase 2 / metabolism
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Gene Expression Regulation, Leukemic*
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Humans
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Integrin beta1 / genetics*
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Integrin beta1 / metabolism
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Jurkat Cells
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Laminin / chemistry
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Laminin / metabolism
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Mice, Nude
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / drug therapy
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / genetics*
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / mortality
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / pathology
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Primary Cell Culture
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Proteoglycans / chemistry
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Proteoglycans / metabolism
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Signal Transduction
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Survival Analysis
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T-Lymphocytes / drug effects
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T-Lymphocytes / metabolism
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T-Lymphocytes / pathology
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Xenograft Model Antitumor Assays
Substances
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Antibiotics, Antineoplastic
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Antibodies, Neutralizing
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Collagen Type I
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Drug Combinations
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Integrin beta1
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Laminin
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Proteoglycans
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RNA, Small Interfering
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matrigel
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Doxorubicin
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Collagen
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Focal Adhesion Kinase 2
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PTK2B protein, human