ALDHHIGH Population Is Regulated by the AKT/ß-Catenin Pathway in a Cervical Cancer Model
Por:
Sarabia-Sánchez M.Á., Alvarado-Ortiz, Eduardo, Toledo-Guzman M.E., Garcia-Carranca, Alejandro, Ortiz-Sanchez, Elizabeth
Publicada:
1 ene 2020
Resumen:
ALDH is an enzyme involved in different cellular processes, including cancer. It has been shown that a cellular subpopulation with high ALDH activity (ALDHHIGH) within a tumor is related to functional capabilities such as stemness, chemoresistance, and tumorigenicity. However, few studies have focused on determining the mechanisms behind ALDH activity within the cells. Previously, our group reported that ALDHHIGH cells have higher tumorigenicity in Cervical Cancer (CC) cell lines. Based on this, we were interested to know the molecular mediators of the ALDHHIGH cells, specifically ß-catenin, inasmuch as ß-catenin is regulated through different pathways, such as Wnt signaling, and that it acts as a transcriptional co-activator involved in cancer progression. In this work, we show that the increase in ALDHHIGH cell percentage is reverted by ß-catenin knockdown. Consistently, upon GSK3-ß inactivation, a negative regulator of ß-catenin, we observed an increase in ALDHHIGH cells. Additionally, we observed a low percentage of cells positive for Fzd receptor, suggesting that in our model there is a low capacity to respond to Wnt ligands. The analysis of ALDHHIGH cells in a sphere formation model demonstrated the active state of AKT. In accordance with this, impairment of AKT activity not only reduced ß-catenin active state, but also the percentage of ALDHHIGH cells. This corroborates that AKT acts upstream of ß-catenin, thus affecting the percentage of ALDHHIGH cells. In conclusion, our results show that ALDHHIGH cells are dependent on ß-catenin, in spite of the Wnt pathway seems to be dispensable, while AKT emerges as central player supporting a mechanism in this important axis that is not yet well known but its analysis improves our understanding of ALDH activity on CC. © Copyright © 2020 Sarabia-Sánchez, Alvarado-Ortiz, Toledo-Guzman, García-Carrancá and Ortiz-Sánchez.
Filiaciones:
Programa de posgrado en Ciencias Bioquímicas, Facultad de Química, Universidad Nacional Autónoma de Mexico, Mexico City, Mexico
Unidad de Investigación Biomédica en Cáncer, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Instituto Nacional de Cancerología, Secretaría de Salud, Mexico City, Mexico
Subdirección de Investigación Básica, Instituto Nacional de Cancerología, Secretaría de Salud, Mexico City, Mexico
Programa de posgrado en Ciencias Biológicas, Facultad de Ciencias, Universidad Nacional Autónoma de Mexico, Mexico City, Mexico
Univ Nacl Autonoma Mexico, Fac Quim, Programa Posgrad Ciencias Bioquim, Mexico City, DF, Mexico
Univ Nacl Autonoma Mexico, Inst Invest Biomed, Unidad Invest Biomed Canc, Mexico City, DF, Mexico
Secretaria Salud Mexico, Inst Nacl Cancerol, Mexico City, DF, Mexico
Secretaria Salud Mexico, Inst Nacl Cancerol, Subdirecc Invest Basica, Mexico City, DF, Mexico
Univ Nacl Autonoma Mexico, Fac Ciencias, Programa Posgrad Ciencias Biol, Mexico City, DF, Mexico
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