DataSheet1_p21-Activated Kinase 1 Promotes Breast Tumorigenesis via Phosphorylation and Activation of the Calcium/Calmodulin-Dependent Protein Kinase II.docx
p21-Activated kinase-1 (Pak1) is frequently overexpressed and/or amplified in human breast cancer and is necessary for transformation of mammary epithelial cells. Here, we show that Pak1 interacts with and phosphorylates the Calcium/Calmodulin-dependent Protein Kinase II (CaMKII), and that pharmacological inhibition or depletion of Pak1 leads to diminished activity of CaMKII. We found a strong correlation between Pak1 and CaMKII expression in human breast cancer samples, and combined inhibition of Pak1 and CaMKII with small-molecule inhibitors was synergistic and induced apoptosis more potently in Her2 positive and triple negative breast cancer (TNBC) cells. Co-adminstration of Pak and CaMKII small-molecule inhibitors resulted in a dramatic reduction of proliferation and an increase in apoptosis in a 3D cell culture setting, as well as an impairment in migration and invasion of TNBC cells. Finally, mice bearing xenografts of TNBC cells showed a significant delay in tumor growth when treated with small-molecule inhibitors of Pak and CaMKII. These data delineate a signaling pathway from Pak1 to CaMKII that is required for efficient proliferation, migration and invasion of mammary epithelial cells, and suggest new therapeutic strategies in breast cancer.
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References
- https://doi.org//10.1007/978-1-0716-0708-4_9
- https://doi.org//10.1038/onc.2017.400
- https://doi.org//10.1042/BC20070109
- https://doi.org//10.1158/0008-5472.CAN-12-4453
- https://doi.org//10.1038/onc.2010.318
- https://doi.org//10.1242/jcs.008037
- https://doi.org//10.1074/jbc.M502306200
- https://doi.org//10.1093/nar/28.1.235
- https://doi.org//10.3748/wjg.v23.i33.6111
- https://doi.org//10.1038/srep33132
- https://doi.org//10.1038/s41467-018-05935-6
- https://doi.org//10.1021/acssynbio.6b00359
- https://doi.org//10.3390/ijms161226116
- https://doi.org//10.1016/S1046-2023%2803%2900032-X
- https://doi.org//10.1016/j.str.2020.06.006
- https://doi.org//10.1186/s12885-016-2769-0
- https://doi.org//10.18632/oncotarget.8320
- https://doi.org//10.1016/S0896-6273%2803%2900428-8
- https://doi.org//10.3390/cancers11101544
- https://doi.org//10.3389/fcell.2019.00269
- https://doi.org//10.1038/ncb1795
- https://doi.org//10.1093/jnci/djj185
- https://doi.org//10.1016/j.gene.2020.144991
- https://doi.org//10.1007/s10549-019-05329-2
- https://doi.org//10.1002/prot.24403
- https://doi.org//10.1038/nprot.2016.169
- https://doi.org//10.1002/jcc.23899
- https://doi.org//10.1093/bioinformatics/btu426
- https://doi.org//10.1007/s10555-020-09922-6
- https://doi.org//10.1016/j.yjmcc.2007.10.016
- https://doi.org//10.1007/s10911-008-9087-3
- https://doi.org//10.1098/rsob.120159
- https://doi.org//10.3390/ijms21249396
- https://doi.org//10.1111/j.1365-2443.2003.00695.x
- https://doi.org//10.1186/s13058-015-0564-5
- https://doi.org//10.1038/nrc3645
- https://doi.org//10.1371/journal.pbio.1000426
- https://doi.org//10.1016/s0960-9822%2897%2970091-5
- https://doi.org//10.1038/onc.2017.143
- https://doi.org//10.3389/fmolb.2021.598218
- https://doi.org//10.3322/caac.21149
- https://doi.org//10.3390/cells9051079
- https://doi.org//10.1186/s13062-015-0103-4
- https://doi.org//10.1016/0006-291x%2891%2992031-e
- https://doi.org//10.3322/caac.21660
- https://doi.org//10.1002/prot.25219
- https://doi.org//10.3390/molecules26030711
- https://doi.org//10.1158/1078-0432.CCR-12-1060
- https://doi.org//10.1186/s12943-017-0720-x
- https://doi.org//10.1016/j.str.2011.10.013
- https://doi.org//10.1038/labinvest.3700658
- https://doi.org//10.2217/fon-2018-0764
- https://doi.org//10.1128/MCB.20.17.6354-6363.2000
- https://doi.org//10.1016/j.bbrc.2004.11.001
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