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Series GSE162475 Query DataSets for GSE162475
Status Public on Mar 31, 2021
Title RNA sequencing reveals that withaferin A reduces overexpression of Bruton's tyrosine kinase in glucocorticoid resistant multiple myeloma cells
Organism Homo sapiens
Experiment type Expression profiling by high throughput sequencing
Summary Multiple myeloma (MM) is an incurable hematological malignancy characterized by the uncontrolled growth of plasma cells in the bone marrow. The major barrier in treating MM is the occurrence of primary and acquired therapy resistance to multiple existing anti-cancer drugs. Often, this therapy resistance is associated with constitutive activation of Bruton tyrosine kinase (BTK) dependent B-cell receptor (BCR) signaling. Novel kinase inhibitors covalently targeting BCR signaling, including the clinically approved BTK inhibitor ibrutinib (IBR) and the preclinical phytochemical Withaferin A (WA), have therefore gained pharmaceutical interest. Remarkably, glucocorticoid (GC)-resistant MM cells overexpressing BTK are more sensitive to WA then to IBR. To further characterize the kinase inhibitor profiles of WA and IBR in GC-resistant MM cells, we applied phosphopeptidome- and transcriptome-specific tyrosine kinome profiling. Our results demonstrate that WA treatment triggers dual inhibition of BCR signaling by transcriptional downregulation and covalent cysteine-dependent kinase inhibition of BTK. Covalent interaction between WA and BTK could further be confirmed by biotin-based affinity purification and confocal imaging microscopy. Altogether, we show that covalent BCR-BTK kinase inhibition by WA represents an attractive strategy to treat GC-resistant MM.
Overall design mRNA profiles of glucocorticoid sensitive MM1.S and glucocorticoid resistant MM1.R cell lines after treatment with withaferin A
Contributor(s) Logie E, Cuypers B, De Neuter N
Citation(s) 33807411
Submission date Dec 01, 2020
Last update date Sep 26, 2021
Contact name Emilie Logie
Organization name University of Antwerp
Department Biomedical Sciences
Street address Universiteitsplein 1
City Wilrijk
State/province Antwerp
ZIP/Postal code 2610
Country Belgium
Platforms (1)
GPL23227 BGISEQ-500 (Homo sapiens)
Samples (12)
GSM4952619 MM1S-T3-P23-UT
GSM4952620 MM1S-T3-P16-UT
GSM4952621 MM1R-T3-P6-UT
BioProject PRJNA681920
SRA SRP295433

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Supplementary file Size Download File type/resource
GSE162475_normalized_gene_counts_DESeq2_WA.txt.gz 1.5 Mb (ftp)(http) TXT
GSE162475_raw_gene_counts_MM1_WA_UNTR.txt.gz 576.7 Kb (ftp)(http) TXT
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Processed data are available on Series record

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