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Molecular and cellular biochemistry
Jan, 2025;480 (1): 505-519.

Folate induces stemness and increases oxygen consumption under glucose deprivation by notch-1 pathway activation in colorectal cancer cell.

Juan Rodríguez Silva, Matías Monsalves-Álvarez, Carlos Sepúlveda, Camila Donoso-Barraza, Rodrigo Troncoso, Sandra Hirsch
Author Information
  1. Juan Rodríguez Silva: Laboratorio de Investigación en Nutrición y Actividad Física (LABINAF), Instituto de Nutrición y Tecnología de los Alimentos (INTA), Universidad de Chile, Santiago, Chile. juan.rodriguez@inta.uchile.cl.
  2. Matías Monsalves-Álvarez: Instituto de Ciencias de la Salud, Universidad de O´Higgins, Rancagua, Chile.
  3. Carlos Sepúlveda: Laboratorio de Investigación en Nutrición y Actividad Física (LABINAF), Instituto de Nutrición y Tecnología de los Alimentos (INTA), Universidad de Chile, Santiago, Chile.
  4. Camila Donoso-Barraza: Laboratorio de Investigación en Nutrición y Actividad Física (LABINAF), Instituto de Nutrición y Tecnología de los Alimentos (INTA), Universidad de Chile, Santiago, Chile.
  5. Rodrigo Troncoso: Laboratorio de Investigación en Nutrición y Actividad Física (LABINAF), Instituto de Nutrición y Tecnología de los Alimentos (INTA), Universidad de Chile, Santiago, Chile.
  6. Sandra Hirsch: Laboratorio de Investigación en Nutrición y Actividad Física (LABINAF), Instituto de Nutrición y Tecnología de los Alimentos (INTA), Universidad de Chile, Santiago, Chile. shirsch@inta.uchile.cl.
PMID: 38536555 DOI: 10.1007/s11010-024-04987-1

Abstract

Evidence for folate's protective effects on neural tube defects led the USA and Chile to start mandatory folic acid (FA) fortification programs, decreasing up to 50%. However, ∼30% of the population consuming fortified foods reach supraphysiologic serum levels. Although controversial, several epidemiological and clinical observations suggest that folate increases cancer risk, giving concern about the risks of FA supplementation. The Cancer stem cells (CSCs) model has been used to explain survival to anticancer therapies. The Notch-1 pathway plays a role in several cancers and is associated with the stemness process. Different studies show that modulation of metabolic pathways regulates stemness capacity in cancer. Supraphysiologic concentrations of FA increase the proliferation of HT-29 cells by Notch-1 activation. However, whether folate can induce a stemness-like phenotype in cancer is not known. We hypothesized that FA protects from glucose deprivation-induced cell death through Notch-1 activation. HT-29 cells were challenged with glucose deprivation at basal (20 nM) and supraphysiological (400 nM) FA and 5-MTHF concentrations. We analyzed changes in stemness-like gene expression, cell death and different energetic metabolic functions. Supraphysiological concentrations of FA increased stemness-like genes, and improved survival and oxygen consumption, inducing AMPK phosphorylation and HSP-70 protein expression. We evaluated the Notch-1 pathway using the DAPT and siRNA as inhibitors, decreasing the stemness-like gene expression and preventing the FA protection against glucose deprivation-induced cell death. Moreover, they decreased oxygen consumption and AMPK phosphorylation. These results suggest that FA protects against glucose deprivation. These effects were associated with AMPK activation, a critical metabolic mediator in nutrient consumption and availability that activates the Notch-1 pathway.

Keywords

Cancer Folate Metabolism Notch-1

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Grants

  1. Proyecto 2016/Proyecto Sochinut-Tetrapak
  2. PhD scholarship 21160444/Comisión Nacional de Investigación Científica y Tecnológica
  3. ENL 01/23/Proyecto Vicerrectoría de Investigación y Desarrollo, Universidad de Chile

MeSH Term

Humans
Receptor, Notch1
Glucose
Folic Acid
Colorectal Neoplasms
HT29 Cells
Neoplastic Stem Cells
Signal Transduction
Oxygen Consumption
Neoplasm Proteins

Chemicals

Receptor, Notch1
Glucose
NOTCH1 protein, human
Folic Acid
Neoplasm Proteins
Journal Article

Word Cloud

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