Glioblastoma (GBM) is the most lethal brain tumor, with a median survival rate of merely 12-16 months after diagnosis. Despite surgical, radiation and chemotherapy treatments, the two-year survival rate for GBM patients is less than 10%. Two major challenges hinder effective treatment: the limited penetration of anti-tumor drugs into GBM tissues because of the blood-brain-barrier; and the rapid development of resistance by GBM cells to almost all treatments. Researchers with The Ohio State University Comprehensive Cancer Center are trying to resolve these two paramount issues to improve outcomes. The study involved both humans and mice. In a previous discovery, the team found that combining antipsychotic drug pimozide with a clinically investigative glutamine metabolism inhibitor, CB-839, can overcome tumor resistance and effectively suppress GBM growth.
Recent studies have underscored the critical roles of specific amino acids, notably, glutamine, methionine, lysine and arginine, in fueling tumor growth. Glutamine and arginine seem particularly important for brain cancer growth. In the experiment, unexpectedly, limiting glutamine availability led to a sharp effect: pimozide at 3 ÎĽM nearly completely eradicated pre-existing cultured cancer colonies and effectively killed glioblastoma cells. Intriguingly, removal of any other amino acids failed to heighten pimozide sensitivity. Notably, cystine, crucial in regulating cellular redox homeostasis was found to be vital for cancer colony maintenance, emphasizing the critical role of redox balance in glioblastoma viability. Notably, pimozide treatment exhibited a remarkable increase in virtually all facets of glutamine metabolism.
These encompassed elevated glutamine uptake, intensified glutaminolysis, heightened reductive carboxylation and the subsequent de novo fatty acid synthesis it drives, augmented tricarboxylic acid (TCA) cycle anaplerosis and intensified synthesis of glutathione (GSH), nucleotides and other amino acids, namely proline and aspartate. These findings strongly suggest that the upregulation of glutamine uptake and consumption potentially serves as a survival mechanism for GBM cells under pimozide treatment. Researchers then analyzed 223 glioma patient samples and identified the previously unknown connection between the glutamine transporter ASCT2 protein and a key lipogenic regulator, SREBP-1. They used a preclinical mouse GBM model to validate this mechanistic link.
They found GBM cells increase glutamine consumption and lipid production at the same time to promote rapid tumor growth. Specifically, they have observed that pimozide effectively curbs the release of cholesterol and fatty acids from lipid droplets and lipoprotein via inhibition of lysosomal function, These effects are expected to starve tumor cells of these crucial lipid building blocks. We recently made the discovery that glutamine uptake and metabolism result in the intracellular release of ammonia that serves as a pivotal activator to stimulate SREBP-1 activation and subsequent lipogenesis. Nevertheless, pimozide treatment alone does not yield the desired efficacy against glioblastoma. The investigation found that GBM’s resistance to treatment with pimozide is attributed to its upregulation of glutamine uptake and consumption.
Pimozide, moreover, increase the cellular ammonia level stimluating glutamine synthesis again. This was accompanied by heightened SREBP-1 activation and increased ASCT2 expression. In contrast, the inhibition of ASCT2 with GPNA, various glutamine utilization enzymes with 6-diazo-5-oxo-L-norleucine (DON), or glutamine synthase with CB-839 led to the abolishment of elevated ammonia levels, SREBP-1 activation and ASCT2 expression, as well as the expression of lipogenic enzymes. Ubsequently, Inhibiting glutamine consumption synergizes with pimozide to induce mitochondrial damage and oxidative stress to blunt GBM cell growth. The combination of targeting glutamine metabolism via ASCT2 or GLS inhibition along with pimozide represents a promising strategy to broadly inhibit glutamine’s functions, limit lipid supplies for tumor cells and effectively kill GBM cells by apoptosis.
The research team believes that their findings will have a significant and lasting impact across many areas including cancer biology, metabolism, signaling transduction and treatment models.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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