Targeting V-ATPase influences cancer cell cholesterol metabolism and biophysical properties - a new option for HCC therapy

Bartel, Karin (2017): Targeting V-ATPase influences cancer cell cholesterol metabolism and biophysical properties - a new option for HCC therapy. Dissertation, LMU München: Fakultät für Chemie und Pharmazie

Abstract

Hepatocellular carcinoma (HCC) is one of the most frequent cancers worldwide and still a major cause of cancer-related death. Despite intensive research, therapy options are limited leaving an urgent need to develop new strategies. Recently, targeting cancer cell lipid and cholesterol metabolism came into focus especially in the context of HCC. Aberrantly increased cholesterol levels cause excessive proliferation, membrane-related mitogenic signaling and a reduction in cell stiffness - factors that favor tumor progression, malignancy and invasive potential. Yet, targeting cholesterol metabolism for cancer therapy is still challenging, leading to a sustained lack of effective therapy options. The V-ATPase inhibitor archazolid was recently implicated in cholesterol metabolism. We report for the first time a novel therapeutic potential of V-ATPase inhibition in cancer by influencing the mechanical phenotype of cancer cells thereby reducing oncogenic Ras signaling. Archazolid inhibits low density lipoprotein (LDL) uptake and induces lysosomal cholesterol trapping, which depletes free cholesterol from the cells and thus leads to an increase in cell stiffness and membrane polarity of cancer cells, while non-malignant hepatocytes remain unaffected. The deficiency of cholesterol in the plasma membrane decreases fluidity and leads to an inhibition of membrane-related Ras signaling resulting in decreased proliferation in vitro and in vivo. By simultaneous application of the lipid-lowering drug simvastatin, a well characterized inhibitor of de novo cholesterol synthesis, a potential escape mechanism by enhanced cholesterol production is prevented, thereby leading to a synergistic growth inhibition in vitro. Hence, we present a novel link between cell biophysical properties and proliferative signaling selectively in malignant HCC cells, which can be targeted synergistically by V-ATPase inhibition and blocking cholesterol synthesis, thus building the basis for an attractive and innovative strategy against HCC.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Themengebiete: 500 Naturwissenschaften und Mathematik ; 500 Naturwissenschaften und Mathematik > 540 Chemie
• Fakultäten: Fakultät für Chemie und Pharmazie
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 29. März 2017
• 1. Bericht­erstatter:in: Vollmar, Angelika