Covalent Cysteine Targeting of Bruton’s Tyrosine Kinase (BTK) Family by Withaferin-A Reduces Survival of Glucocorticoid-Resistant Multiple Myeloma MM1 Cells
Abstract
:Simple Summary
Abstract
1. Introduction
2. Results
2.1. GC Therapy Resistance in Multiple Myeloma Is Associated with Hyperactivation of Tyrosine Kinases
2.2. The Tyrosine Kinase Inhibitor Profile of Withaferin A and Ibrutinib Show a High Degree of Similarity
2.3. WA Inhibits BCR-BTK Kinase Activity by Transcriptional Downregulation and Covalent Cysteine-Dependent Targeting of BTK
2.4. Covalent C481 Targeting of BTK by WA in Hinge-6 Domain of the Protein Kinase Cysteinome Classification Reduces Survival of Glucocorticoid Resistant Multiple Myeloma MM1 Cells
3. Discussion
4. Materials and Methods
4.1. Cell Culture and Cell Viability Assays
4.2. Cell Lysis and Peptide Array-Based TK Activity Profiling
4.3. cDNA Conversion Quantitative Real-Time PCR
4.4. RNA Extraction and RNA Sequencing
4.5. Antibodies and Reagents
4.6. Cell Viability after WA Washout
4.7. Protein Extraction and Western Immunoblot Analysis
4.8. WA-Biotin-Based Affinity Purification
4.9. Immunofluorescence Confocal Microscopy
4.10. Covalent Docking of WA with BTK
4.11. Cell Transfections and BRET Measurements
4.12. Nucleofection of siBTK and C481S BTK
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Gene Ontology Term | Symbol | Gene ID | Name | Log2FC | p-Adj. |
---|---|---|---|---|---|
ECM and cell–cell adhesion | RELN * | 5649 | Reelin | 2.9 | 7.4 × 10−160 |
PLXNB2 | 23654 | Plexin B2 | 1.8 | 7.1 × 10−96 | |
PODXL2 * | 50512 | Podocalyxin like 2 | 2.6 | 6.8 × 10−83 | |
ESAM | 90952 | Endothelial cell adhesion molecule | 2.0 | 1.7 × 10−80 | |
PRKX * | 5613 | Protein kinase X-linked | 1.1 | 8.1 × 10−79 | |
ACP5 | 54 | Acid phosphatase 5, tartrate-resistant | 4.8 | 2.0 × 10−77 | |
GPCR signaling | GNG7 | 2788 | G protein subunit gamma 7 | 1.5 | 5.7 × 10−99 |
UTS2R | 2837 | Urotensin 2 receptor | 1.9 | 5.4 × 10−77 | |
BCR signaling | BTK * | 695 | Bruton’s tyrosine kinase | 2.8 | 1.5 × 10−216 |
TNFRSF8 | 943 | TNF receptor superfamily member 8 | 3.7 | 6.9 × 10−93 | |
CD52 | 1043 | CD52 molecule | 3.5 | 5.6 × 10−83 | |
mRNA/protein stability | CTAG2 | 30848 | Cancer/testis antigen 2 | 8.5 | 4.0 × 10−168 |
LINC01518 | 101929397 | Long intergenic non-protein Coding RNA 1518 | 7.9 | 1.4 × 10−147 | |
CMTR1 | 23070 | Cap methyltransferase 1 | −1.1 | 9.6 × 10−115 | |
TMEM25 | 84866 | Transmembrane protein 25 | 4.8 | 6.0 × 10−79 | |
Cell cycle regulation | CDKN2A | 1029 | Cyclin-dependent kinase inhibitor 2A | 9.4 | 1.7 × 10−210 |
Cytoskeleton | TUBB4A | 10382 | Tubulin beta 4A class IVa | 3.6 | 6.1 × 10−165 |
Inflammation | NLRP11 | 204801 | NLR family pyrin domain containing 11 | 4.9 | 1.2 × 10−220 |
Transmembrane transport | SLC38A5 | 92745 | Solute carrier family 38 member 5 | 1.8 | 1.7 × 10−92 |
ABCG2* | 9429 | ATP-binding cassette subfamily G member 2 | 5.6 | 2.0 × 10−84 |
Site | Subsite | Representative Kinases |
---|---|---|
Gatekeeper region | GK | MOK |
GK + 1 | SgK494 | |
GK − 1 | MAP2K4, MKK3, MAP2K6, KHS1, KHS2, GCK | |
DFG region | DFG + 1 | MAP3K8, MOS, MAP3K4, PINK1 |
DFG + 2 | PKCz, PKCi, AKT1, AKT2, AKT3, PKCg, SGK1F, SGK2 | |
DFG − 1 | PBK, TGFbR2, CDKL3, CDKL2, PRP4, MNK2, MNK1 | |
Glycine rich loop region | Glycineloop | WNK4, WNK1, WNK2, WNK3, HER3 |
Glycineloop 1 | ZAK | |
Glycineloop 2 | SgK496, MEKK1, PLK2, PLK3, PLK1, RSK1 | |
Glycineloop 3 | SgK493 | |
Glycineloop5 | FGFR1, FGFR2, FGFR3, FGFR4 | |
Hinge binding region | Hinge 1 | FGFR4, TTK, MAPKAPK2, MAPKAPK3 |
Hinge 2 | IKKa, IKKb, LKB1, NEK4, Wee1, SLK, FLT4, KDR | |
Hinge 3 | Ron, FGR, SgK494, Kit, CSFR, FLT3 | |
Hinge 4 | SgK110, BubR1, LKB1, TBK1 | |
Hinge 5 | PINK1, EphB3 | |
Hinge 6 | MAP2K7, TEC, TXK, ITK, BTK, BMX, BLK, HER2, EGFR, HER4, JAK3 | |
Hinge 7 | JNK1, JNK2, JNK3 | |
Roof region | Roof sheet | HER3 |
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Logie, E.; Chirumamilla, C.S.; Perez-Novo, C.; Shaw, P.; Declerck, K.; Palagani, A.; Rangarajan, S.; Cuypers, B.; De Neuter, N.; Mobashar Hussain Urf Turabe, F.; et al. Covalent Cysteine Targeting of Bruton’s Tyrosine Kinase (BTK) Family by Withaferin-A Reduces Survival of Glucocorticoid-Resistant Multiple Myeloma MM1 Cells. Cancers 2021, 13, 1618. https://doi.org/10.3390/cancers13071618
Logie E, Chirumamilla CS, Perez-Novo C, Shaw P, Declerck K, Palagani A, Rangarajan S, Cuypers B, De Neuter N, Mobashar Hussain Urf Turabe F, et al. Covalent Cysteine Targeting of Bruton’s Tyrosine Kinase (BTK) Family by Withaferin-A Reduces Survival of Glucocorticoid-Resistant Multiple Myeloma MM1 Cells. Cancers. 2021; 13(7):1618. https://doi.org/10.3390/cancers13071618
Chicago/Turabian StyleLogie, Emilie, Chandra S. Chirumamilla, Claudina Perez-Novo, Priyanka Shaw, Ken Declerck, Ajay Palagani, Savithri Rangarajan, Bart Cuypers, Nicolas De Neuter, Fazil Mobashar Hussain Urf Turabe, and et al. 2021. "Covalent Cysteine Targeting of Bruton’s Tyrosine Kinase (BTK) Family by Withaferin-A Reduces Survival of Glucocorticoid-Resistant Multiple Myeloma MM1 Cells" Cancers 13, no. 7: 1618. https://doi.org/10.3390/cancers13071618