Metabolic reprogramming underlies differential effects of folate depletion in non-metastatic and metastatic claudin-low breast cancer

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  • February 26, 2019
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  • Chen, Xuewen
    • Affiliation: College of Arts and Sciences, Department of Biology
Abstract
  • Cells undergo metabolic reprogramming during oncogenic transformation and cancer progression. Folate one-carbon cycle plays an important role in providing the necessary substrates for proliferating cancer cells. Aberrant folate metabolism has been implicated in the development of several cancer types, though underlying mechanisms remain unclear. Our lab has previously demonstrated that a folate-restricted diet increased the growth and invasion of orthotopically transplanted murine non-metastatic mesenchymal claudin-low breast cancer cells (M-Wnt) in vivo. In contrast, it decreased the growth and lung metastasis of transplanted metM-Wntlung cells, a metastatic subclone of the M-Wnt tumor. The current study explored whether metabolic reprogramming of the two cell lines affects their differential response to folate withdrawal. The non-metastatic and metastatic cells differed in several metabolic pathways, including energetics and autophagy. To examine the effect of long-term folate depletion on M-Wnt and metM-Wntlung cell metabolism in vitro, the two cell lines were grown in standard or folate-depleted media for 14 days. Both M-Wnt and metM-Wntlung cells exhibited increased autophagy and oxidative stress following long-term folate depletion. However, following long-term folate depletion, only metM-Wntlung cells showed decreased viability and increased apoptosis. These results suggest that these cells underwent metabolic reprogramming in response to nutrient stress. While the non-metastatic M-Wnt cells were able to withstand nutrient starvation through adaptation involving glutathione metabolism and autophagy, the metastatic cells were less adaptable, and thus folate restriction prevented their growth. This study highlighted that metabolic reprogramming during tumor progression to metastasis may change cells’ adaptability under nutrient stress, and folate restriction as a nutrient stress can assess tumors’ metabolic phenotypes.
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  • In Copyright
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  • Funding: Breast Cancer Research Foundation and National Cancer Institute
  • Funding: Honors Undergraduate Research Fund
Advisor
  • Hursting, Stephen
Degree
  • Bachelor of Science
Academic concentration
  • Biology
Honors level
  • Honors
Degree granting institution
  • University of North Carolina at Chapel Hill
Graduation year
  • 2018
Language
  • English

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