TY - JOUR
T1 - p21-Activated Kinase 1 Promotes Breast Tumorigenesis via Phosphorylation and Activation of the Calcium/Calmodulin-Dependent Protein Kinase II
AU - Saldivar-Cerón, Héctor I.
AU - Villamar-Cruz, Olga
AU - Wells, Claire M.
AU - Oguz, Ibrahim
AU - Spaggiari, Federica
AU - Chernoff, Jonathan
AU - Patiño-López, Genaro
AU - Huerta-Yepez, Sara
AU - Montecillo-Aguado, Mayra
AU - Rivera-Pazos, Clara M.
AU - Loza-Mejía, Marco A.
AU - Vivar-Sierra, Alonso
AU - Briseño-Díaz, Paola
AU - Zentella-Dehesa, Alejandro
AU - Leon-Del-Rio, Alfonso
AU - López-Saavedra, Alejandro
AU - Padierna-Mota, Laura
AU - Ibarra-Sánchez, María de Jesús
AU - Esparza-López, José
AU - Hernández-Rivas, Rosaura
AU - Arias-Romero, Luis E.
N1 - Funding Information:
This work was supported by grants from Consejo Nacional de Ciencia y Tecnología (CONACyT) CB 252444 and from UNAM (PAPIIT IN213218 and IN211022) to LA-R. HS-C was supported by CONACyT doctoral fellowship 588927.
Publisher Copyright:
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.
PY - 2022/1/17
Y1 - 2022/1/17
N2 - 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.
AB - 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.
KW - breast cancer
KW - kinase
KW - migration
KW - small molecule inhibitor
KW - synergy
UR - http://www.scopus.com/inward/record.url?scp=85123912253&partnerID=8YFLogxK
U2 - 10.3389/fcell.2021.759259
DO - 10.3389/fcell.2021.759259
M3 - Article
AN - SCOPUS:85123912253
SN - 2296-634X
VL - 9
JO - Frontiers in Cell and Developmental Biology
JF - Frontiers in Cell and Developmental Biology
M1 - 759259
ER -