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3 Publications visible to you, out of a total of 3
Targeting aldolase A in hepatocellular carcinoma leads to imbalanced glycolysis and energy stress due to uncontrolled FBP accumulation

Abstract (Expand)

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 …etabolic 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.

Authors: Marteinn T. Snaebjornsson, Philipp Poeller, Daria Komkova, Florian Röhrig, Lisa Schlicker, Alina M. Winkelkotte, Adriano B. Chaves-Filho, Kamal M. Al-Shami, Carolina Dehesa Caballero, Ioanna Koltsaki, Felix C. E. Vogel, Roberto Carlos Frias-Soler, Ramona Rudalska, Jessica D. Schwarz, Elmar Wolf, Daniel Dauch, Ralf Steuer, Almut Schulze

Date Published: 1st Feb 2025

Publication Type: Journal

Hepatocyte apical bulkheads provide a mechanical means to oppose bile pressure

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Hepatocytes grow their apical surfaces anisotropically to generate a 3D network of bile canaliculi (BC). BC elongation is ensured by apical bulkheads, membrane extensions that traverse the lumen and … the lumen and connect juxtaposed hepatocytes. We hypothesize that apical bulkheads are mechanical elements that shape the BC lumen in liver development but also counteract elevated biliary pressure. Here, by resolving their structure using STED microscopy, we found that they are sealed by tight junction loops, connected by adherens junctions, and contain contractile actomyosin, characteristics of mechanical function. Apical bulkheads persist at high pressure upon microinjection of fluid into the BC lumen, and laser ablation demonstrated that they are under tension. A mechanical model based on ablation results revealed that apical bulkheads double the pressure BC can hold. Apical bulkhead frequency anticorrelates with BC connectivity during mouse liver development, consistent with predicted changes in biliary pressure. Our findings demonstrate that apical bulkheads are load-bearing mechanical elements that could protect the BC network against elevated pressure.

Authors: Maarten P. Bebelman, Matthew J. Bovyn, Carlotta M. Mayer, Julien Delpierre, Ronald Naumann, Nuno P. Martins, Alf Honigmann, Yannis Kalaidzidis, Pierre A. Haas, Marino Zerial

Date Published: 3rd Apr 2023

Publication Type: Journal

Raf kinase inhibitor protein mediates myocardial fibrosis under conditions of enhanced myocardial oxidative stress.

Abstract (Expand)

Fibrosis is a hallmark of maladaptive cardiac remodelling. Here we report that genome-wide quantitative trait locus (QTL) analyses in recombinant inbred mouse lines of C57BL/6 J and DBA2/J strains … identified Raf Kinase Inhibitor Protein (RKIP) as genetic marker of fibrosis progression. C57BL/6 N-RKIP(-/-) mice demonstrated diminished fibrosis induced by transverse aortic constriction (TAC) or CCl(4) (carbon tetrachloride) treatment compared with wild-type controls. TAC-induced expression of collagen Ialpha2 mRNA, Ki67(+) fibroblasts and marker of oxidative stress 8-hydroxyguanosine (8-dOHG)(+) fibroblasts as well as the number of fibrocytes in the peripheral blood and bone marrow were markedly reduced in C57BL/6 N-RKIP(-/-) mice. RKIP-deficient cardiac fibroblasts demonstrated decreased migration and fibronectin production. This was accompanied by a two-fold increase of the nuclear accumulation of nuclear factor erythroid 2-related factor 2 (Nrf2), the main transcriptional activator of antioxidative proteins, and reduced expression of its inactivators. To test the importance of oxidative stress for this signaling, C57BL/6 J mice were studied. C57BL/6 J, but not the C57BL/6 N-strain, is protected from TAC-induced oxidative stress due to mutation of the nicotinamide nucleotide transhydrogenase gene (Nnt). After TAC surgery, the hearts of Nnt-deficient C57BL/6 J-RKIP(-/-) mice revealed diminished oxidative stress, increased left ventricular (LV) fibrosis and collagen Ialpha2 as well as enhanced basal nuclear expression of Nrf2. In human LV myocardium from both non-failing and failing hearts, RKIP-protein correlated negatively with the nuclear accumulation of Nrf2. In summary, under conditions of Nnt-dependent enhanced myocardial oxidative stress induced by TAC, RKIP plays a maladaptive role for fibrotic myocardial remodeling by suppressing the Nrf2-related beneficial effects.

Authors: A. Kazakov, R. A. Hall, C. Werner, T. Meier, A. Trouvain, S. Rodionycheva, A. Nickel, F. Lammert, C. Maack, M. Bohm, U. Laufs

Date Published: 6th Sep 2018

Publication Type: Journal

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