Biology subjects

Gunter, J. H.

Publications and source records attributed to Gunter, J. H..

4 recordsLinked to original sources

bioRxiv2024

Valine Catabolism Drives Bioenergetic and Lipogenic Fuel Plasticity in Prostate Cancer

Metabolic reprogramming is a hallmark of cancer and fundamental for disease progression. The remodelling of oxidative phosphorylation and enhanced lipogenesis are key characteristics of prostate cancer (PCa). Recently, succinate-dependent mitochondrial reprogramming was identified in high-grade prostate tumours with upregulation of enzymes associated with branched-chain amino acid (BCAA) catabolism. We hypothesised that the degradation of BCAAs, particularly valine may play a critical role in anapleurotic refuelling of the mitochondrial succinate pool. Through suppression of valine availability, we report strongly reduced lipid content despite compensatory upregulation of fatty acid uptake, indicating valine is an important lipogenic fuel in PCa. Inhibition of the enzyme 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) also resulted in selective inhibition of cellular proliferation of malignant but not benign prostate cells and impaired succinate production. In combination with a comprehensive multi-omic investigation of patient and cell line data, our work highlights a therapeutic target for selective inhibition of metabolic reprogramming in PCa.

cancer biology↗

bioRxiv2023

Epidermal Growth Factor potentiates EGFR(Y992/1173)-mediated therapeutic response of triple negative breast cancer cells to cold atmospheric plasma-activated medium

Cold atmospheric plasma (CAP) holds promise as a cancer-specific treatment that selectively kills basal-like breast cancer cells. We used CAP-activated media (PAM) to capture the multi-modal chemical species of CAP. Specific antibodies, small molecule inhibitors and CRISPR/Cas9 gene-editing approaches showed an essential role for receptor tyrosine kinases, especially epidermal growth factor (EGF) receptor, in mediating triple negative breast cancer (TNBC) cell responses to PAM. EGF also dramatically enhanced the sensitivity and specificity of PAM against TNBC cells. Site-specific phospho-EGFR analysis, signal transduction inhibitors and reconstitution of EGFR-depleted cells with EGFR-mutants confirmed the role of phospho-tyrosines 992/1173 and phospholipase C gamma signaling in upregulating levels of reactive oxygen species above the apoptotic threshold. EGF-triggered EGFR activation enhanced the sensitivity and selectivity of PAM effects on TNBC cells, such that a strategy based on the synergism of CAP and EGF therapy may provide new opportunities to improve the clinical management of TNBC.

cancer biology↗

bioRxiv2021

Isomeric lipid signatures reveal compartmentalised fatty acid metabolism in cancer

1.0Cellular energy and biomass demands of cancer drive a complex dynamic between uptake of extracellular fatty acids (FA) and de novo synthesis. Given that oxidation of de novo synthesised FAs for energy would result in net-energy loss, there is an implication that FAs from these two sources must have distinct metabolic fates - however hitherto FAs were considered part of a common pool. To probe FA metabolic partitioning, cancer cells were supplemented with stable-isotope labelled FAs. Structural analysis of the resulting glycerophospholipids revealed that labelled FAs from uptake were largely incorporated to canonical (sn-)positions on the glycerol backbone. Surprisingly, labelled FA uptake disrupted canonical isomer patterns of the unlabelled lipidome and induced repartitioning of n-3 and n-6 polyunsaturated-FAs into glycerophospholipid classes. These structural changes evidence differences in the metabolic fate of FAs derived from uptake or de novo sources and demonstrate unique signalling and remodelling behaviours usually hidden to conventional lipidomics. HighlightsO_LILipid isomers reveal discrete metabolic compartmentalisation in cancer C_LIO_LIFAs derived from uptake and de novo synthesis have different metabolic fates C_LIO_LIStearate uptake signals for PUFA (n-3 and n-6) repartitioning between lipid classes C_LIO_LIsn-positional isomers are a marker for aberrant lipid metabolism C_LI

cancer biology↗

bioRxiv2019

The long non-coding RNA GHSROS reprograms prostate cancer cell lines toward a more aggressive phenotype

It is now appreciated that long non-coding RNAs (lncRNAs) are important players in the orchestration of cancer progression. In this study we characterized GHSROS, a human lncRNA gene on the opposite DNA strand (antisense) to the ghrelin receptor gene, in prostate cancer. The lncRNA was upregulated by prostate tumors from different clinical datasets. Consistently, transcriptome data revealed that GHSROS alters the expression of cancer-associated genes. Functional analyses in vitro showed that GHSROS mediates tumor growth, migration, and survival and resistance to the cytotoxic drug docetaxel. Increased cellular proliferation of GHSROS-overexpressing PC3, DU145, and LNCaP prostate cancer cell lines in vitro was recapitulated in a subcutaneous xenograft model. Conversely, in vitro antisense oligonucleotide inhibition of the lncRNA reciprocally regulated cell growth and migration, and gene expression. Notably, GHSROS modulates the expression of PPP2R2C, the loss of which may drive androgen receptor pathway-independent prostate tumor progression in a subset of prostate cancers. Collectively, our findings suggest that GHSROS can reprogram prostate cancer cells toward a more aggressive phenotype and that this lncRNA may represent a potential therapeutic target.

cancer biology↗