AUTHOR=Saldivar-Cerón Héctor I. , Villamar-Cruz Olga , Wells Claire M. , Oguz Ibrahim , Spaggiari Federica , Chernoff Jonathan , Patiño-López Genaro , Huerta-Yepez Sara , Montecillo-Aguado Mayra , Rivera-Pazos Clara M. , Loza-Mejía Marco A. , Vivar-Sierra Alonso , Briseño-Díaz Paola , Zentella-Dehesa Alejandro , Leon-Del-Rio Alfonso , López-Saavedra Alejandro , Padierna-Mota Laura , Ibarra-Sánchez María de Jesús , Esparza-López José , Hernández-Rivas Rosaura , Arias-Romero Luis E. TITLE=p21-Activated Kinase 1 Promotes Breast Tumorigenesis via Phosphorylation and Activation of the Calcium/Calmodulin-Dependent Protein Kinase II JOURNAL=Frontiers in Cell and Developmental Biology VOLUME=9 YEAR=2022 URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2021.759259 DOI=10.3389/fcell.2021.759259 ISSN=2296-634X ABSTRACT=

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.