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Downregulation of Smad4 expression confers chemoresistance against imatinib mesylate to chronic myeloid leukemia K562 cells
- Source :
- Hematology, Vol 27, Iss 1, Pp 43-52 (2022)
- Publication Year :
- 2021
-
Abstract
- Objective: Imatinib mesylate (IM), a tyrosine kinase inhibitor, exhibits clinically prominent effects against chronic myeloid leukemia (CML); however, a few patients have shown resistance to IM treatment, resulting in disease progression. Smad4 is a tumor inhibitor that transduces TGF-β signaling and modulates genomic stability. Previous studies have indicated that decreased Smad4 expression played a bidirectional role in chemosensitivity in many types of cancers. Therefore, this study aims to evaluate the association between IM sensitivity and decreased Smad4 expression in human CML K562 cells. Methods: Bone marrow (BM) samples were acquired from the patients prior to treatment. qRT-PCR, Western Blotting (WB), colony formation assay (CFA), and apoptosis assay were used to detect relevant indices. Results: Smad4 expression was downregulated in the bone marrow and plasma of patients with multidrug-resistant CML as well as IM-resistant K562 (K562R) cells compared with samples collected from CML patients and K562 cells. Smad4 overexpression inhibited IM-treated K562R cell proliferation and augmented apoptosis, whereas Smad4 silencing promoted viability and inhibited apoptosis in IM-treated K562 cells. In addition, Smad4 expression was inversely correlated with laminin subunit gamma 1 (LAMC1) expression. The upregulation or downregulation of LAMC1 expression partially abolished the effect of Smad4 overexpression or silencing on the IM resistance of CML cells. Conclusion: The downregulation of Smad4 expression might induce drug resistance in CML cells and displayed a possible mechanism through which Smad4 modulates CML cell survival and apoptosis upon IM treatment.
- Subjects :
- proliferation
chemoresistance
Gene Expression
Apoptosis
Hematology
k562
Flow Cytometry
lamc1
imatinib
Drug Resistance, Neoplasm
hemic and lymphatic diseases
Gene Knockdown Techniques
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Imatinib Mesylate
Humans
Diseases of the blood and blood-forming organs
ATP Binding Cassette Transporter, Subfamily B, Member 1
smad4
RC633-647.5
cml
K562 Cells
neoplasms
Protein Kinase Inhibitors
Smad4 Protein
Subjects
Details
- ISSN :
- 16078454
- Volume :
- 27
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Hematology (Amsterdam, Netherlands)
- Accession number :
- edsair.doi.dedup.....c63949d5d95db9ea92fbc8129082083b