Two recent publications have indicated that an unassuming glycosphingolipid that has long been associated with rare metabolic disorders may contribute to heart disease and cancer, the two leading causes of death in the United States.
Glycosphingolipids (GSLs) are complex membrane lipids that play diverse roles in cell communication, especially during development. Patients with Gaucher or Fabry disease, or other lysosomal storage disorders lack one or more enzymes in the GSL pathway. Without these enzymes, normal substrates build up to toxic levels, leading to debilitating pathologies, including neurodegeneration.
Gaucher disease, the most common of the lysosomal storage disorders with a prevalence of 1 in 57,000 births, is caused by a mutation in the gene for β-glucocerebrosidase, which eliminates or impairs the enzyme, resulting in accumulation of its substrate, glucosylceramide. Some subtypes of this disease have been successfully treated with recombinant enzyme replacement therapy, although the overall effectiveness of the treatment is limited by the enzyme’s inability to enter the central nervous system. An alternative treatment under investigation, known as substrate reduction therapy, uses small molecule inhibitors to block formation of glucosylceramide by glucosylceramide synthase (GCS).
Recently, GCS has also been proposed as a potential therapeutic target for cancer and cardiovascular disease.
In a study led by Sumita Mishra and Subroto Chatterjee at Johns Hopkins University School of Medicine, investigators showed that administration of the GCS inhibitor, 1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP), attenuated the atherosclerotic symptoms of ApoE knockout mice that were fed high fat/high cholesterol diets. The PDMP-treated mice showed a dose dependent decrease in myocardial GSL accumulation accompanied by a return to normal ventricular mass. The team demonstrated a potential mechanism for the GSL-dependent effects by showing that phosphorylation of mitogen-activated protein kinase (MAPK) was reduced in the PDMP-treated mice. Activation of p38 MAPK has a significant impact on gene expression patterns in the heart, and the pathway has long been implicated in cardiac hypertrophy. The researchers concluded that reducing synthesis of glycosphingolipids with pathological effects could be a new approach for preventing cardiac hypertrophy.
In the cancer study, a team led by Andreas Tyler at Umea University in Sweden investigated the role of GCS in development of resistance to chemotherapeutics in non-small cell lung cancer and malignant pleural mesothelioma. Increased ceramide levels contribute to the anti-proliferative and anti-apoptotic effects of chemotherapeutics. However, the tumor cells respond by increasing GCS activation, thereby converting ceramides into GSLs. This creates somewhat of a perfect storm, as it not only enhances proliferation and attenuates apoptosis, but GSLs also stimulate drug efflux by activating expression of the multidrug resistance pump, MDR1. In addition to pumping out chemotherapeutics, MDR1 pumps GSL precursors into the lumen of the ER, where GCS is located, and in this way is believed to contribute to accumulation of globotriaosylceramide (Gb3), a GSL that has been associated with invasion and metastasis in a number of cancers. Tyler and his team found that the GCS inhibitor PDMP eliminated increased cell surface Gb3 expression in lung cancer and mesothelioma cell lines with acquired cisplatin resistance, and augmented the cytotoxicity of cisplatin with the resistant mesothelial cells. The investigators conclude that inhibition of GCS may be way to reverse acquired cisplatin resistance in non-small cell lung cancer and malignant pleuralmesothelioma.
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