p21-Activated Kinase 1 Promotes Breast Tumorigenesis via Phosphorylation and Activation of the Calcium/Calmodulin-Dependent Protein Kinase II

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-RivasLuis E. Arias-Romero*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)

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.

Original languageEnglish
Article number759259
JournalFrontiers in Cell and Developmental Biology
Volume9
Early online date17 Jan 2022
DOIs
Publication statusPublished - 17 Jan 2022

Keywords

  • breast cancer
  • kinase
  • migration
  • small molecule inhibitor
  • synergy

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