Coculture in vitro with endothelial cells induces cytarabine resistance of acute myeloid leukemia cells in a VEGF-A/VEGFR-2 signaling–independent manner
| Autor: | Akira Yamauchi, Keisuke Kitakaze, Shuichiro Okamoto, Kei Miyano, Hitomi Kato, Mizuho Kajikawa, Momoe Itsumi, Chikage Kawai, Futoshi Kuribayashi |
|---|---|
| Rok vydání: | 2022 |
| Předmět: |
Vascular Endothelial Growth Factor A
Antimetabolites Antineoplastic Indoles Biophysics Angiogenesis Inhibitors HL-60 Cells Models Biological Biochemistry Cell Line Gene Knockout Techniques Jurkat Cells Paracrine signalling Cell Movement medicine Humans Phosphorylation Molecular Biology Neovascularization Pathologic Gene Expression Regulation Leukemic Chemistry Cell Cycle Cytarabine Endothelial Cells Myeloid leukemia U937 Cells Cell Biology medicine.disease Vascular Endothelial Growth Factor Receptor-2 Coculture Techniques Endothelial stem cell Leukemia Myeloid Acute Vascular endothelial growth factor A Leukemia medicine.anatomical_structure Drug Resistance Neoplasm Apoptosis Cancer research Bone marrow K562 Cells Signal Transduction medicine.drug |
| Zdroj: | Biochemical and Biophysical Research Communications. 587:78-84 |
| ISSN: | 0006-291X |
| DOI: | 10.1016/j.bbrc.2021.11.090 |
| Popis: | An interaction between acute myeloid leukemia (AML) cells and endothelial cells in the bone marrow seems to play a critical role in chemosensitivity on leukemia treatment. The endothelial niche reportedly enhances the paracrine action of the soluble secretory proteins responsible for chemoresistance in a vascular endothelial growth factor A (VEGF-A)/VEGF receptor 2 (VEGFR-2) signaling pathway–dependent manner. To further investigate the contribution of VEGF-A/VEGFR-2 signaling to the chemoresistance of AML cells, a biochemical assay system in which the AML cells were cocultured with human endothelial EA.hy926 cells in a monolayer was developed. By coculture with EA.hy926 cells, this study revealed that the AML cells resisted apoptosis induced by the anticancer drug cytarabine. SU4312, a VEGFR-2 inhibitor, attenuated VEGFR-2 phosphorylation and VEGF-A/VEGFR-2 signaling–dependent endothelial cell migration; thus, this inhibitor was observed to block VEGF-A/VEGFR-2 signaling. Interestingly, this inhibitor did not reverse the chemoresistance. When VEGFR-2 was knocked out in EA.hy926 cells using the CRISPR–Cas9 system, the cytarabine-induced apoptosis of AML cells did not significantly change compared with that of wild-type cells. Thus, coculture-induced chemoresistance appears to be independent of VEGF-A/VEGFR-2 signaling. When the transwell, a coculturing device, separated the AML cells from the EA.hy926 cells in a monolayer, the coculture-induced chemoresistance was inhibited. Given that the migration of VEGF-A/VEGFR-2 signaling–dependent endothelial cells is necessary for the endothelial niche formation in the bone marrow, VEGF-A/VEGFR-2 signaling contributes to chemoresistance by mediating the niche formation process, but not to the chemoresistance of AML cells in the niche. |
| Databáze: | OpenAIRE |
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