Biology subjects

Woodhouse, B.

Publications and source records attributed to Woodhouse, B..

2 recordsLinked to original sources

bioRxiv2025

Insights into anterograde trafficking and pharmacological chaperoning of Cannabinoid Receptor 2 (CB2)

Cannabinoid Receptor 2 (CB2) is a promising therapeutic target for modulating inflammation. Canonical signalling responses to receptor ligands are critically dependent on cell surface receptor expression. However, it is also now appreciated that intracellular G protein-coupled receptors can contribute to signalling responses and influence functional outcomes. Therefore, understanding how the subcellular distribution of receptors is controlled is also highly pertinent. CB2 is observed to be expressed at the cell surface as well as having a considerable proportion expressed intracellularly. Despite this distribution being well established, little is known about the regulation of CB2 anterograde trafficking and subcellular distribution. We report that sustained treatment with a range of CB2 agonists and inverse agonists stimulates a distinct population of CB2 to be delivered to the cell surface, at various expression levels and despite agonists concurrently internalising cell surface CB2. We present evidence that this ligand-stimulated anterograde trafficking is a result of CB2 agonists, as well as inverse agonists, acting as pharmacological chaperones. We also report that a di-lysine (KK) motif in the CB2 C-terminal tail is required for basal delivery to the cell surface. Corroborating the hypothesis that CB2 ligands can act as pharmacological chaperones, sustained CB2 ligand stimulation induces cell surface expression of the mutated receptor and alters maturation states as measured by western blotting. Our finding that prolonged exposure to CB2 ligands can induce CB2 cell surface delivery via pharmacological chaperoning may well have important implications for optimal design of CB2-targeted therapeutics.

pharmacology and toxicology↗

bioRxiv2017

Recurrent loss of heterozygosity correlates with clinical outcome in pancreatic neuroendocrine cancer

Pancreatic neuroendocrine tumors (pNETs) are uncommon cancers arising from pancreatic islet cells. Analysis of gene mutation, copy number and RNA expression of 57 sporadic pNETs showed that pNET genomes are dominated by aneuploidy. Remarkably, ~25% of pNETs had genomes characterized by recurrent loss of heterozygosity (LoH) of the same 10 chromosomes, accompanied by bi-allelic MEN1 inactivation, and these cases had generally poor clinical outcome. Another ~25% of all pNETs had chromosome 11 LoH and bi-allelic MEN1 inactivation, lacking the recurrent LoH pattern - these had universally good clinical outcome. Some level of aneuploidy was common, and overall ~80% of pNETs had LoH of [≥]1 chromosome. This aneuploidy led to changes in RNA expression at the level of whole chromosomes and allowed pathogenic germline variants (e.g. ATM) to be expressed unopposed, inactivating downstream tumor suppressor pathways. Some pNETs appear to utilize VHL gene methylation or mutation to activate pseudo-hypoxia. Contrary to expectation neither tumor morphology within well-differentiated pNETs nor single gene mutation had significant associations with clinical outcome, nor did expression of RNAs reflecting the activity of immune, differentiation, proliferative or tumor suppressor pathways. MEN1 was the only statistically significant recurrently mutated driver gene in pNETs. Only one pNET had clearly oncogenic and actionable SNVs (in PTEN and FLCN) confirmed by corroborating RNA expression changes. The two distinct patterns of aneuploidy described here, associated with markedly poor and good clinical outcome respectively, define a novel oncogenic mechanism and the first route to genomic precision oncology for this tumor type.

cancer biology↗