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@ARTICLE{Snaebjrnsson:298171,
author = {M. T. Snaebjörnsson$^*$ and P. Poeller$^*$ and D. Komkova
and F. Röhrig and L. Schlicker$^*$ and A. Winkelkotte$^*$
and A. B. Chaves-Filho$^*$ and K. M. Al-Shami$^*$ and C. D.
Caballero$^*$ and I. Koltsaki$^*$ and F. C. E. Vogel$^*$ and
R. C. Frias-Soler$^*$ and R. Rudalska and J. D. Schwarz and
E. Wolf and D. Dauch and R. Steuer and A. Schulze$^*$},
title = {{T}argeting aldolase {A} in hepatocellular carcinoma leads
to imbalanced glycolysis and energy stress due to
uncontrolled {FBP} accumulation.},
journal = {Nature metabolism},
volume = {7},
number = {2},
issn = {2522-5812},
address = {[London]},
publisher = {Springer Nature},
reportid = {DKFZ-2025-00190},
pages = {348-366},
year = {2025},
note = {#EA:A410#LA:A410# / 2025 Feb;7(2):348-366},
abstract = {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.},
cin = {A410},
ddc = {610},
cid = {I:(DE-He78)A410-20160331},
pnm = {311 - Zellbiologie und Tumorbiologie (POF4-311)},
pid = {G:(DE-HGF)POF4-311},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:39833612},
doi = {10.1038/s42255-024-01201-w},
url = {https://inrepo02.dkfz.de/record/298171},
}