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.
Keywords: breast cancer; kinase; migration; small molecule inhibitor; synergy.
Copyright © 2022 Saldivar-Cerón, Villamar-Cruz, Wells, Oguz, Spaggiari, Chernoff, Patiño-López, Huerta-Yepez, Montecillo-Aguado, Rivera-Pazos, Loza-Mejía, Vivar-Sierra, Briseño-Díaz, Zentella-Dehesa, Leon-Del-Rio, López-Saavedra, Padierna-Mota, Ibarra-Sánchez, Esparza-López, Hernández-Rivas and Arias-Romero.