학술논문
p21-Activated Kinase 1 Promotes Breast Tumorigenesis via Phosphorylation and Activation of the Calcium/Calmodulin-Dependent Protein Kinase II
Document Type
article
Author
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
Source
Frontiers in Cell and Developmental Biology, Vol 9 (2022)
Subject
Language
English
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.