DataSheet1_p21-Activated Kinase 1 Promotes Breast Tumorigenesis via Phosphorylation and Activation of the Calcium/Calmodulin-Dependent Protein Kinase .docx (527.29 kB)
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DataSheet1_p21-Activated Kinase 1 Promotes Breast Tumorigenesis via Phosphorylation and Activation of the Calcium/Calmodulin-Dependent Protein Kinase II.docx

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posted on 17.01.2022, 11:43 authored by Héctor I. Saldivar-Cerón, Olga Villamar-Cruz, Claire M. Wells, Ibrahim Oguz, Federica Spaggiari, Jonathan Chernoff, Genaro Patiño-López, Sara Huerta-Yepez, Mayra Montecillo-Aguado, Clara M. Rivera-Pazos, Marco A. Loza-Mejía, Alonso Vivar-Sierra, Paola Briseño-Díaz, Alejandro Zentella-Dehesa, Alfonso Leon-Del-Rio, Alejandro López-Saavedra, Laura Padierna-Mota, María de Jesús Ibarra-Sánchez, José Esparza-López, Rosaura Hernández-Rivas, Luis E. Arias-Romero

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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