Combinatorial targeting of glutamine metabolism and lysosomal-based lipid metabolism effectively suppresses glioblastoma.

Antipsychotic drugs have been shown to have antitumor effects but have had limited potency in the clinic. Here, we unveil that pimozide inhibits lysosome hydrolytic function to suppress fatty acid and cholesterol release in glioblastoma (GBM), the most lethal brain tumor. Unexpectedly, GBM develops resistance to pimozide by boosting glutamine consumption and lipogenesis.

Combined Vorinostat and Chloroquine Inhibit Sodium-Iodide Symporter Endocytosis and Enhance Radionuclide Uptake In Vivo.

Purpose: Patients with aggressive thyroid cancer are frequently failed by the central therapy of ablative radioiodide (RAI) uptake, due to reduced plasma membrane (PM) localization of the sodium/iodide symporter (NIS). We aimed to understand how NIS is endocytosed away from the PM of human thyroid cancer cells, and whether this was druggable in vivo.

Experimental Design: Informed by analysis of endocytic gene expression in patients with aggressive thyroid cancer, we used mutagenesis, NanoBiT interaction assays, cell surface biotinylation assays, RAI uptake, and NanoBRET to understand the mechanisms of NIS endocytosis in transformed cell lines and patient-derived human primary thyroid cells.

In vivo RNA-seq and ChIP-seq analyses show an obligatory role for the C terminus of p53 in conferring tissue-specific radiation sensitivity.

Thymus and spleen, in contrast to liver, are radiosensitive tissues in which p53-dependent apoptosis is triggered after whole-body radiation in vivo. Combined RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) analyses of radiation-treated mouse organs identifies both shared and tissue-specific p53 transcriptional responses. As expected, the p53 targets shared among thymus and spleen are enriched in apoptotic targets.

Molecular Dynamics Refinement of Open State Serotonin 5-HT Receptor Structures.

Pentameric ligand-gated ion channels play an important role in mediating fast neurotransmissions. As a member of this receptor family, cation-selective 5-HT receptors are a clinical target for treating nausea and vomiting associated with chemotherapy and radiation therapy (Thompson and Lummis, 2006). Multiple cryo-electron microscopy (cryo-EM) structures of 5-HT receptors have been determined in distinct functional states (e.

Electrostatic Contributions to the Binding Free Energy of Nicotine to the Acetylcholine Binding Protein.

Biomolecular binding relies on specific attractive interactions between two partner molecules, including electrostatics, dispersion, hydrophobicity, and solvation. Assessing the contributions of electrostatic interactions to binding is key to the understanding of ligand binding mechanisms and the design of improved biomolecular binders. For example, nicotine is a well-known agonist of nicotinic acetylcholine receptors (nAChRs), but the molecular mechanisms for the differential action of nicotine on brain and muscle nAChRs remain elusive.

Ammonia stimulates SCAP/Insig dissociation and SREBP-1 activation to promote lipogenesis and tumour growth.

Tumorigenesis is associated with elevated glucose and glutamine consumption, but how cancer cells can sense their levels to activate lipid synthesis is unknown. Here, we reveal that ammonia, released from glutamine, promotes lipogenesis via activation of sterol regulatory element-binding proteins (SREBPs), endoplasmic reticulum-bound transcription factors that play a central role in lipid metabolism. Ammonia activates the dissociation of glucose-regulated, N-glycosylated SREBP-cleavage-activating protein (SCAP) from insulin-inducible gene protein (Insig), an endoplasmic reticulum-retention protein, leading to SREBP translocation and lipogenic gene expression.