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VLA-4 Induces Chemoresistance of T Cell Acute Lymphoblastic Leukemia Cells via PYK2-Mediated Drug Efflux
SIMPLE SUMMARY: Cellular adhesion plays an important role in the development of resistance to chemotherapy (chemoresistance) that represents a major hurdle in the treatment of leukemia and which is a major cause for patient relapse. In this study, we evaluated if cell adhesion to the molecule VCAM-1...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8307050/ https://www.ncbi.nlm.nih.gov/pubmed/34298726 http://dx.doi.org/10.3390/cancers13143512 |
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author | Berrazouane, Sofiane Doucet, Alexie Boisvert, Marc Barabé, Frédéric Aoudjit, Fawzi |
author_facet | Berrazouane, Sofiane Doucet, Alexie Boisvert, Marc Barabé, Frédéric Aoudjit, Fawzi |
author_sort | Berrazouane, Sofiane |
collection | PubMed |
description | SIMPLE SUMMARY: Cellular adhesion plays an important role in the development of resistance to chemotherapy (chemoresistance) that represents a major hurdle in the treatment of leukemia and which is a major cause for patient relapse. In this study, we evaluated if cell adhesion to the molecule VCAM-1, which is present in the leukemia microenvironment, can favour the chemoresistance of T acute lymphoblastic leukemia (T-ALL). Our results showed that adhesion of T-ALL cells to VCAM-1 via their receptor VLA-4 induces the resistance of T-ALL cells to doxorubicin by activating the signaling protein PYK2 but not FAK. VLA-4/PYK2 signaling did so by inducing the efflux of doxorubicin. However, adhesion of T-ALL cells to fibronectin via the receptor VLA-5 did not activate PYK2 and had no effect on doxorubicin resistance. These findings suggest that targeting the VLA-4/PYK2 pathway could overcome T-ALL chemoresistance and reduce the risk of patient relapse. ABSTRACT: Cell adhesion plays a critical role in the development of chemoresistance, which is a major issue in anti-cancer therapies. In this study, we have examined the role of the VLA-4 integrin, a major adhesion molecule of the immune system, in the chemoresistance of T-ALL cells. We found that attachment of Jurkat and HSB-2 T-ALL cells to VCAM-1, a VLA-4 ligand, inhibits doxorubicin-induced apoptosis. However, their adhesion to fibronectin, which is mainly mediated via VLA-5, had no effect. Even the presence of the chemoattractant SDF1α (Stromal cell-derived factor-1α), which enhances the adhesion of T-ALL cells to fibronectin, did not modify the sensitivity of the cells attached on fibronectin towards doxorubicin-induced apoptosis. Mechanistically, we found that VLA-4 promoted T-ALL chemoresistance by inducing doxorubicin efflux. Our results showed that cell adhesion to both fibronectin and VCAM-1-induced Focal adhesion kinase (FAK) phosphorylation in T-ALL cells. However, only cell adhesion to VCAM-1 led to PYK2 phosphorylation. Inhibition studies indicated that FAK is not involved in doxorubicin efflux and chemoresistance, whereas PYK2 inhibition abrogated both VLA-4-induced doxorubicin efflux and chemoresistance. Together, these results indicate that the VLA-4/PYK2 pathway could participate in T-ALL chemoresistance and its targeting could be beneficial to limit/avoid chemoresistance and patient relapse. |
format | Online Article Text |
id | pubmed-8307050 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-83070502021-07-25 VLA-4 Induces Chemoresistance of T Cell Acute Lymphoblastic Leukemia Cells via PYK2-Mediated Drug Efflux Berrazouane, Sofiane Doucet, Alexie Boisvert, Marc Barabé, Frédéric Aoudjit, Fawzi Cancers (Basel) Article SIMPLE SUMMARY: Cellular adhesion plays an important role in the development of resistance to chemotherapy (chemoresistance) that represents a major hurdle in the treatment of leukemia and which is a major cause for patient relapse. In this study, we evaluated if cell adhesion to the molecule VCAM-1, which is present in the leukemia microenvironment, can favour the chemoresistance of T acute lymphoblastic leukemia (T-ALL). Our results showed that adhesion of T-ALL cells to VCAM-1 via their receptor VLA-4 induces the resistance of T-ALL cells to doxorubicin by activating the signaling protein PYK2 but not FAK. VLA-4/PYK2 signaling did so by inducing the efflux of doxorubicin. However, adhesion of T-ALL cells to fibronectin via the receptor VLA-5 did not activate PYK2 and had no effect on doxorubicin resistance. These findings suggest that targeting the VLA-4/PYK2 pathway could overcome T-ALL chemoresistance and reduce the risk of patient relapse. ABSTRACT: Cell adhesion plays a critical role in the development of chemoresistance, which is a major issue in anti-cancer therapies. In this study, we have examined the role of the VLA-4 integrin, a major adhesion molecule of the immune system, in the chemoresistance of T-ALL cells. We found that attachment of Jurkat and HSB-2 T-ALL cells to VCAM-1, a VLA-4 ligand, inhibits doxorubicin-induced apoptosis. However, their adhesion to fibronectin, which is mainly mediated via VLA-5, had no effect. Even the presence of the chemoattractant SDF1α (Stromal cell-derived factor-1α), which enhances the adhesion of T-ALL cells to fibronectin, did not modify the sensitivity of the cells attached on fibronectin towards doxorubicin-induced apoptosis. Mechanistically, we found that VLA-4 promoted T-ALL chemoresistance by inducing doxorubicin efflux. Our results showed that cell adhesion to both fibronectin and VCAM-1-induced Focal adhesion kinase (FAK) phosphorylation in T-ALL cells. However, only cell adhesion to VCAM-1 led to PYK2 phosphorylation. Inhibition studies indicated that FAK is not involved in doxorubicin efflux and chemoresistance, whereas PYK2 inhibition abrogated both VLA-4-induced doxorubicin efflux and chemoresistance. Together, these results indicate that the VLA-4/PYK2 pathway could participate in T-ALL chemoresistance and its targeting could be beneficial to limit/avoid chemoresistance and patient relapse. MDPI 2021-07-14 /pmc/articles/PMC8307050/ /pubmed/34298726 http://dx.doi.org/10.3390/cancers13143512 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Berrazouane, Sofiane Doucet, Alexie Boisvert, Marc Barabé, Frédéric Aoudjit, Fawzi VLA-4 Induces Chemoresistance of T Cell Acute Lymphoblastic Leukemia Cells via PYK2-Mediated Drug Efflux |
title | VLA-4 Induces Chemoresistance of T Cell Acute Lymphoblastic Leukemia Cells via PYK2-Mediated Drug Efflux |
title_full | VLA-4 Induces Chemoresistance of T Cell Acute Lymphoblastic Leukemia Cells via PYK2-Mediated Drug Efflux |
title_fullStr | VLA-4 Induces Chemoresistance of T Cell Acute Lymphoblastic Leukemia Cells via PYK2-Mediated Drug Efflux |
title_full_unstemmed | VLA-4 Induces Chemoresistance of T Cell Acute Lymphoblastic Leukemia Cells via PYK2-Mediated Drug Efflux |
title_short | VLA-4 Induces Chemoresistance of T Cell Acute Lymphoblastic Leukemia Cells via PYK2-Mediated Drug Efflux |
title_sort | vla-4 induces chemoresistance of t cell acute lymphoblastic leukemia cells via pyk2-mediated drug efflux |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8307050/ https://www.ncbi.nlm.nih.gov/pubmed/34298726 http://dx.doi.org/10.3390/cancers13143512 |
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