TY  - JOUR
AU  - Snaebjörnsson, Marteinn Thor
AU  - Poeller, Philipp
AU  - Komkova, Daria
AU  - Röhrig, Florian
AU  - Schlicker, Lisa
AU  - Winkelkotte, Alina
AU  - Chaves-Filho, Adriano B
AU  - Al-Shami, Kamal M
AU  - Caballero, Carolina Dehesa
AU  - Koltsaki, Ioanna
AU  - Vogel, Felix Christian Eduard
AU  - Frias-Soler, Roberto Carlos
AU  - Rudalska, Ramona
AU  - Schwarz, Jessica D
AU  - Wolf, Elmar
AU  - Dauch, Daniel
AU  - Steuer, Ralf
AU  - Schulze, Almut
TI  - Targeting aldolase A in hepatocellular carcinoma leads to imbalanced glycolysis and energy stress due to uncontrolled FBP accumulation.
JO  - Nature metabolism
VL  - 7
IS  - 2
SN  - 2522-5812
CY  - [London]
PB  - Springer Nature
M1  - DKFZ-2025-00190
SP  - 348-366
PY  - 2025
N1  - #EA:A410#LA:A410# / 2025 Feb;7(2):348-366
AB  - Increased glycolytic flux is a hallmark of cancer; however, an increasing body of evidence indicates that glycolytic ATP production may be dispensable in cancer, as metabolic plasticity allows cancer cells to readily adapt to disruption of glycolysis by increasing ATP production via oxidative phosphorylation. Using functional genomic screening, we show here that liver cancer cells show a unique sensitivity toward aldolase A (ALDOA) depletion. Targeting glycolysis by disrupting the catalytic activity of ALDOA led to severe energy stress and cell cycle arrest in murine and human hepatocellular carcinoma cell lines. With a combination of metabolic flux analysis, metabolomics, stable-isotope tracing and mathematical modelling, we demonstrate that inhibiting ALDOA induced a state of imbalanced glycolysis in which the investment phase outpaced the payoff phase. Targeting ALDOA effectively converted glycolysis from an energy producing into an energy-consuming process. Moreover, we found that depletion of ALDOA extended survival and reduced cancer cell proliferation in an animal model of hepatocellular carcinoma. Thus, our findings indicate that induction of imbalanced glycolysis by targeting ALDOA presents a unique opportunity to overcome the inherent metabolic plasticity of cancer cells.
LB  - PUB:(DE-HGF)16
C6  - pmid:39833612
DO  - DOI:10.1038/s42255-024-01201-w
UR  - https://inrepo02.dkfz.de/record/298171
ER  -