English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Global: Zendy Plus annual

Presents the access of premium content as premium feature

Premium Content

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Insights

Presents the pdf analysis as premium feature

PDF Analysis

Presents the zaia usage as premium feature

ZAIA

Global: Zendy Tools annual

Global: Zendy Free Plan

Global: Zendy Tools monthly

Global: Zendy Plus monthly

Background Deregulated glucose metabolism is a critical component of cancer growth and survival, clinically evident via FDG-PET imaging of enhanced glucose uptake in tumor nodules. Tumor cells utilize glucose in a variety of interconnected biochemical pathways to generate energy, anabolic precursors, and other metabolites necessary for growth. Glucagon-stimulated gluconeogenesis opposes glycolysis, potentially representing a pathway-specific strategy for targeting glucose metabolism in tumor cells. Here, we test the hypothesis of whether glucagon signaling can activate gluconeogenesis to reduce tumor proliferation in models of liver cancer. Methods The glucagon receptor, GCGR, was overexpressed in liver cancer cell lines consisting of a range of etiologies and genetic backgrounds. Glucagon signaling transduction was measured by cAMP ELISAs, western blots of phosphorylated PKA substrates, and qPCRs of relative mRNA expression of multiple gluconeogenic enzymes. Lastly, cell proliferation and apoptosis assays were performed to quantify the biological effect of glucagon/GCGR stimulation. Results Signaling analyses in SNU398 GCGR cells treated with glucagon revealed an increase in cAMP abundance and phosphorylation of downstream PKA substrates, including CREB. qPCR data indicated that none of the three major gluconeogenic genes,  G6PC ,  FBP1 , or  PCK1 , exhibit significantly higher mRNA levels in SNU398 GCGR cells when treated with glucagon; however, this could be partially increased with epigenetic inhibitors. In glucagon-treated SNU398 GCGR cells, flow cytometry analyses of apoptotic markers and growth assays reproducibly measured statistically significant reductions in cell viability. Finally, proliferation experiments employing siCREB inhibition showed no reversal of cell death in SNU398 GCGR cells treated with glucagon, indicating the effects of glucagon in this setting are independent of CREB. Conclusions For the first time, we report a potential tumor suppressive role for glucagon/GCGR in liver cancer. Specifically, we identified a novel cell line-specific phenotype, whereby glucagon signaling can induce apoptosis via an undetermined mechanism. Future studies should explore the potential effects of glucagon in diabetic liver cancer patients.

Glucagon signaling via supraphysiologic GCGR can reduce cell viability without stimulating gluconeogenic gene expression in liver cancer cells