Cell death & disease, 2019-05, Vol.10 (5), p.357, Article 357
2019
Details
- Autor(en) / Beteiligte
- Titel
- Beta1 integrin blockade overcomes doxorubicin resistance in human T-cell acute lymphoblastic leukemia
- Ist Teil von
- Cell death & disease, 2019-05, Vol.10 (5), p.357, Article 357
- Ort / Verlag
- England: Springer Nature B.V
- Erscheinungsjahr
- 2019
- Link zum Volltext
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 2041-4889eISSN: 2041-4889DOI: 10.1038/s41419-019-1593-2Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6494825
- Format
- –
- Schlagworte
- Acute lymphoblastic leukemia, Animals, Antibiotics, Antineoplastic - pharmacology, Antibodies, Neutralizing - pharmacology, Apoptosis - drug effects, Bone marrow, Cell adhesion, Cell adhesion & migration, Cell Adhesion - drug effects, Cell Line, Tumor, Chemoresistance, Collagen (type I), Collagen - chemistry, Collagen - metabolism, Collagen Type I - chemistry, Collagen Type I - metabolism, Doxorubicin, Doxorubicin - pharmacology, Drug Combinations, Drug Resistance, Neoplasm - genetics, Extracellular matrix, Extracellular Matrix - chemistry, Extracellular Matrix - metabolism, Focal Adhesion Kinase 2 - antagonists & inhibitors, Focal Adhesion Kinase 2 - genetics, Focal Adhesion Kinase 2 - metabolism, Gene Expression Regulation, Leukemic, Humans, Integrin beta1 - genetics, Integrin beta1 - metabolism, Integrins, Jurkat Cells, Laminin - chemistry, Laminin - metabolism, Leukemia, Lymphatic leukemia, Lymphocytes T, Mice, Nude, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - drug therapy, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - genetics, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - mortality, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - pathology, Primary Cell Culture, Proline, Proline-rich tyrosine kinase 2, Protein-tyrosine kinase, Proteoglycans - chemistry, Proteoglycans - metabolism, RNA, Small Interfering - genetics, RNA, Small Interfering - metabolism, Signal Transduction, siRNA, Survival Analysis, T-Lymphocytes - drug effects, T-Lymphocytes - metabolism, T-Lymphocytes - pathology, Therapeutic applications, Xenograft Model Antitumor Assays, Xenografts