Biology subjects

Brackenbury, W. J.

Publications and source records attributed to Brackenbury, W. J..

21 records · Page 2Linked to original sources

bioRxiv2021

Sodium accumulation in breast cancer predicts malignancy and treatment response

Breast cancer is the leading cause of cancer-related death in women worldwide. Development of novel noninvasive diagnostic and predictive pathophysiological biomarkers would represent a significant clinical improvement. Here, we explored the utility of non-invasive 23Na MRI to profile tumour physiology using preclinical mouse models of breast cancer. We establish that tissue Na+ concentration ([Na+]) is elevated vs non-tumour regions across multiple different tumour models. Ex vivo SBFI fluorescence imaging corroborated that this elevation in tumour [Na+] is due to increased intracellular [Na+]. Effective treatment with cytotoxic chemotherapy reduced tumour tissue [Na+], but was not detected by 1H diffusion-weighted imaging (DWI). Moreover, combining 23Na MRI and DWI measurements enabled superior classification accuracy of tumour vs non-tumour regions compared to either parameter alone. Quantification of breast tumour tissue [Na+] using 23Na MRI thus represents a novel, accurate, non-invasive diagnostic and predictive imaging biomarker.

cancer biology↗

bioRxiv2020

Inhibitory effect of eslicarbazepine acetate and S-licarbazepine on Nav1.5 channels

Eslicarbazepine acetate (ESL) is a dibenzazepine anticonvulsant approved as adjunctive treatment for partial-onset epileptic seizures. Following first pass hydrolysis of ESL, S-licarbazepine (S-Lic) represents around 95 % of circulating active metabolites. S-Lic is the main enantiomer responsible for anticonvulsant activity and this is proposed to be through the blockade of voltage-gated Na+ channels (VGSCs). ESL and S-Lic both have a voltage-dependent inhibitory effect on the Na+ current in N1E-115 neuroblastoma cells expressing neuronal VGSC subtypes including Nav1.1, Nav1.2, Nav1.3, Nav1.6 and Nav1.7. ESL has not been associated with cardiotoxicity in healthy volunteers, although a prolongation of the electrocardiographic PR interval has been observed, suggesting that ESL may also inhibit cardiac Nav1.5 isoform. However, this has not previously been studied. Here, we investigated the electrophysiological effects of ESL and S-Lic on Nav1.5 using whole-cell patch clamp recording. We interrogated two model systems: (1) MDA-MB-231 metastatic breast carcinoma cells, which endogenously express the neonatal Nav1.5 splice variant, and (2) HEK-293 cells stably over-expressing the adult Nav1.5 splice variant. We show that both ESL and S-Lic inhibit transient and persistent Na+ current, hyperpolarise the voltage-dependence of fast inactivation, and slow the recovery from channel inactivation. These findings highlight, for the first time, the potent inhibitory effects of ESL and S-Lic on the Nav1.5 isoform, suggesting a possible explanation for the prolonged PR interval observed in patients on ESL treatment. Given that numerous cancer cells have also been shown to express Nav1.5, and that VGSCs potentiate invasion and metastasis, this study also paves the way for future investigations into ESL and S-Lic as potential invasion inhibitors.

pharmacology and toxicology↗

bioRxiv2019

Voltage-dependent activation of Rac1 by Nav1.5 channels promotes cell migration

Ion channels can regulate the plasma membrane potential (Vm) and cell migration as a result of altered ion flux. However, the mechanism by which Vm regulates motility remains unclear. Here, we show that the Nav1.5 sodium channel carries persistent inward Na+ current which depolarizes the resting Vm at the timescale of minutes. This Nav1.5-dependent Vm depolarization increases Rac1 colocalization with phosphatidylserine, to which it is anchored at the leading edge of migrating cells, promoting Rac1 activation. A genetically-encoded FRET biosensor of Rac1 activation shows that depolarization-induced Rac1 activation results in acquisition of a motile phenotype. By identifying Nav1.5-mediated Vm depolarization as a regulator of Rac1 activation, we link ionic and electrical signaling at the plasma membrane to small GTPase-dependent cytoskeletal reorganization and cellular migration. We uncover a novel and unexpected mechanism for Rac1 activation, which fine tunes cell migration in response to ionic and/or electric field changes in the local microenvironment.

cell biology↗