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

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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, \(\sim\)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.

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Funding

Juan Rodríguez Silva was supported by Proyecto SOCHINUT-Tetra Pak 2016 and CONICYT Ph. D scholarship N° 21160444. Rodrigo Troncoso was supported by Proyecto Vicerrectoría de Investigación y Desarrollo (VID) de la Universidad de Chile, ENL01/23.

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  1. Laboratorio de Investigación en Nutrición y Actividad Física (LABINAF), Instituto de Nutrición y Tecnología de los Alimentos (INTA), Universidad de Chile, Santiago, Chile

    Juan Rodríguez Silva, Carlos Sepúlveda, Camila Donoso-Barraza, Rodrigo Troncoso & Sandra Hirsch

  2. Instituto de Ciencias de la Salud, Universidad de O´Higgins, Rancagua, Chile

    Matías Monsalves-Álvarez

  3. Geroscience Center for Brain Health and Metabolism (GERO), Santiago, Chile

    Matías Monsalves-Álvarez

  4. Advanced Center for Chronic Diseases (ACCDiS), Universidad de Chile, Santiago, Chile

    Rodrigo Troncoso

Authors
  1. Juan Rodríguez Silva
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  2. Matías Monsalves-Álvarez
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  3. Carlos Sepúlveda
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  4. Camila Donoso-Barraza
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  5. Rodrigo Troncoso
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  6. Sandra Hirsch
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Contributions

JRS conceived the study, performed experiments, analyzed the data and wrote the manuscript. MM-A performed experiments and wrote the manuscript. CS analyzed the data and wrote the manuscript. CD-B performed experiments. RT conceived the study, analyzed the data and wrote the manuscript. SH conceived the study, performed experiments, analyzed the data and wrote the manuscript. All authors reviewed the manuscript.

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Correspondence to Juan Rodríguez Silva or Sandra Hirsch.

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Rodríguez Silva, J., Monsalves-Álvarez, M., Sepúlveda, C. et al. Folate induces stemness and increases oxygen consumption under glucose deprivation by notch-1 pathway activation in colorectal cancer cell. Mol Cell Biochem (2024). https://doi.org/10.1007/s11010-024-04987-1

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  • DOI: https://doi.org/10.1007/s11010-024-04987-1

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