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Fluvastatin plus dipyridamole suppresses canine hemangiosarcoma growth in patient-derived xenograft models through lactate dehydrogenase-associated cholesterol/lipid metabolism

ABSTRACT: Tumor cells exhibit distinct metabolic features such as the Warburg effect, consuming abundant glucose and producing large amounts of lactate even under aerobic conditions. Lactate dehydrogenase (LDH) plays a central role in regulating the intracellular lactate levels. Canine hemangiosarcoma (HSA) is a highly aggressive malignant tumor arising from vascular endothelial cells, and no effective targeted therapies have been established due to limited understanding of its molecular pathogenesis. The endothelial cells also rely on glycolysis for energy sources, although the involvement of lactate and LDH in HSA remains unknown. In this study, we investigated the role of lactate metabolism and LDH in HSA. The dual LDHA/LDHB inhibitor (R)-GNE-140 significantly suppressed HSA cell proliferation in vitro and reduced the expression of cholesterol-related genes. Knockout experiments showed that loss of LDHA, but not LDHB, was associated with decreased expression of cholesterol-related genes and reduced lipid droplet formation in HSA cells. Based on the association, we tested fluvastatin with or without dipyridamole to evaluate their anti-tumor efficacy using PDX models. While fluvastatin monotherapy had limited effect, the combined treatment significantly inhibited tumor growth. These findings suggest that LDH may link to cholesterol metabolism and that cholesterol pathway inhibition could offer a therapeutic opportunity in HSA.

ORGANISM(S): Canis lupus familiaris

PROVIDER: GSE314239 | GEO | 2026/08/05

REPOSITORIES: GEO

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Project description:This experiment was conducted to identify target genes of the peroxisome proliferator-activated receptor beta (PPARb) in skeletal muscle of transgenic mice that overexpressed PPARb. The following abstract from the submitted manuscript describes the major findings of this work. The Nuclear Receptor Transcription Factor PPARbeta/delta Programs Muscle Glucose Metabolism. Zhenji Gan, Eileen Burkart-Hartman, Dong-Ho Han, Brian Finck, Teresa C. Leone, John Holloszy, and Daniel P. Kelly. To identify new gene regulatory pathways controlling skeletal muscle energy metabolism, comparative studies were conducted on muscle-specific transgenic mouse lines expressing the nuclear receptors, PPARalpha (MCK-PPARalpha) or PPARbeta/delta (MCK-PPARbeta/delta). MCK-PPARbeta/delta mice are known to have enhanced exercise performance whereas MCK-PPARalpha mice perform at low levels. Transcriptional profiling revealed that the lactate dehydrogenase (Ldh)b/Ldha gene expression ratio is increased in MCK-PPARbeta/delta muscle, an isoenzyme shift that diverts pyruvate into the mitochondrion for the final steps of glucose oxidation. PPARbeta/delta gain- and loss-of-function studies in skeletal myotubes demonstrated that PPARbeta/delta, but not PPARalpha, interacts with the exercise inducible kinase, AMP-activated protein kinase (AMPK), to synergistically activate Ldhb gene transcription by cooperating with myocyte enhancer factor 2A (MEF2A), in a PPARbeta/delta ligand-independent manner. MCK-PPARbeta/delta muscle was shown to have high glycogen stores, increased levels of GLUT4, and augmented capacity for mitochondrial pyruvate oxidation suggesting a broad reprogramming of glucose utilization pathways. Lastly, exercise studies demonstrated that MCK-PPARbeta/delta mice had lower circulating levels of lactate compared to non-transgenic controls, while exhibiting supranormal performance on a high intensity exercise regimen. These results identify a transcriptional regulatory mechanism that increases capacity for muscle glucose utilization in a pattern that resembles the effects of exercise training. Keywords: muscle, exercise, nuclear receptors, glucose metabolism, gene regulation RNA from two wild-type (non-transgenic (NTG)) and two PPARbeta overexpressing (MCK-PPARb) mice was analyzed. Two replicates of each are provided.

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Fluvastatin plus dipyridamole suppresses canine hemangiosarcoma growth in patient-derived xenograft models through lactate dehydrogenase-associated cholesterol/lipid metabolism

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