Triple Negative Breast Cancer and Breast Epithelial Cells Differentially Reprogram Glucose and Lipid Metabolism upon Treatment with Triterpenic Acids


Plant-derived pentacyclic triterpenic acids (TAs) have gained increasing attention due to their multiple biological activities. Betulinic acid (BA) and ursolic acid (UA) modulate diverse pathways in carcinogenesis, offering increased changes of success in refractory cancers, such as triple negative breast cancer (TNBC). The present work aimed to assess the metabolic effects of BA and UA in MDA-MB-231 breast cancer cells (TNBC model), as well as in MCF-10A non-cancer breast epithelial cells, with a view to unveiling the involvement of metabolic reprogramming in cellular responses to these TAs. Cell viability and cell cycle analyses were followed by assessment of changes in the cells exo- and endometabolome through(1)H NMR analysis of cell culture medium supernatants, aqueous and organic cell extracts. In MDA-MB-231 cells, BA was suggested to induce a transient upregulation of glucose consumption and glycolytic conversion, tricarboxylic acid (TCA) cycle intensification, and hydrolysis of neutral lipids, while UA effects were much less pronounced. In MCF-10A cells, boosting of glucose metabolism by the two TAs was accompanied by diversion of glycolytic intermediates to the hexosamine biosynthetic pathway (HBP) and the synthesis of neutral lipids, possibly stored in detoxifying lipid droplets. Additionally, breast epithelial cells intensified pyruvate consumption and TCA cycle activity, possibly to compensate for oxidative impairment of pyruvate glycolytic production. This study provided novel insights into the metabolic effects of BA and UA in cancer and non-cancer breast cells, thus improving current understanding of the action of these compounds at the molecular level.



subject category

Biochemistry & Molecular Biology


Guerra, AR; Paulino, AF; Castro, MM; Oliveira, H; Duarte, MF; Duarte, IF

our authors


This work was developed within the scope of the projects CICECO-Aveiro Institute of Materials (UIDB/50011/2020 & UIDP/50011/2020), CESAM (UIDP/50017/2020 & UIDB/50017/2020) and MED-Mediterranean Institute for Agriculture, Environment and Development (UIDB/05183/2020), financed by national funds through the Foundation for Science and Technology/MCTES, Portugal. Funding to the project NEucBark-New valorization strategies for Eucalyptus spp. Bark Extracts (PTDC/AGR-FOR/3187/2012) by FEDER through COMPETE and by national funds through FCT is also acknowledged. The NMR spectrometers are part of the National NMR Network (PTNMR) and are partially supported by Infrastructure Project No 022161 (co-financed by FEDER through COMPETE 2020, POCI and PORL and FCT through PIDDAC). A.G. acknowledges the FCT-awarded grant SFRH/BD/98635/2013. H.O and I.F.D acknowledge FCT/MCTES for research contracts under the `Stimulus to Scientific Employment' (CEECIND/04050/2017 and CEECIND/02387/2018, respectively).

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