Related Experiment Video

Updated: Jul 1, 2026

Utilizing 18F-FDG PET/CT Imaging and Quantitative Histology to Measure Dynamic Changes in the Glucose Metabolism in Mouse Models of Lung Cancer
06:51

Utilizing 18F-FDG PET/CT Imaging and Quantitative Histology to Measure Dynamic Changes in the Glucose Metabolism in Mouse Models of Lung Cancer

Published on: July 21, 2018

GLP-1 receptor agonist targets an AMPKα1-HIF1α-PFKFB3 metabolic vulnerability and enhances Lenvatinib response in

Takayuki Noma1,2, Yuan Li1,3, Yuma Wada2

  • 1Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope, Biomedical Research Center, Monrovia, California, USA.

NPJ Precision Oncology
|June 29, 2026
PubMed

Insights

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) show anti-tumor effects in liver cancer by targeting metabolic vulnerabilities. Combining GLP-1RAs with Lenvatinib overcomes resistance and inhibits tumor growth.

Area of Science:

  • Oncology
  • Metabolic Regulation
  • Pharmacology

Background:

  • Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are used for diabetes and obesity, with emerging evidence for anti-tumor properties.
  • Hepatocellular carcinoma (HCC) exhibits metabolic reprogramming and enhanced glycolysis, contributing to resistance against therapies like Lenvatinib.

Purpose of the Study:

  • To investigate the anti-tumor effects of GLP-1RAs in HCC.
  • To determine if GLP-1RAs can modulate cancer-specific metabolic vulnerabilities and enhance sensitivity to Lenvatinib.

Main Methods:

  • Analysis of Lenvatinib-resistant HCC cells to identify molecular changes in metabolic pathways.
  • Treatment of resistant HCC models with a GLP-1RA, alone and in combination with Lenvatinib.
  • Assessment of key signaling pathways including AMPKα1, HIF-1α, and PFKFB3, and evaluation of glycolytic activity and apoptosis.

Main Results:

  • Lenvatinib-resistant HCC cells showed suppressed AMPKα1 and increased HIF-1α and PFKFB3, indicating enhanced glycolysis.
  • GLP-1RA treatment normalized AMPKα1 activity and suppressed the HIF-1α/PFKFB3 axis, reducing glycolysis and increasing apoptosis.
  • Combination therapy with GLP-1RA and Lenvatinib significantly inhibited tumor growth in resistant HCC models.

Conclusions:

  • The AMPKα1/HIF-1α/PFKFB3 axis is a metabolic vulnerability in Lenvatinib-resistant HCC.
  • GLP-1RAs can overcome Lenvatinib resistance by targeting this metabolic pathway.
  • GLP-1RA-based combination therapies represent a promising strategy for treating resistant HCC.

More Related Videos

Drug-Induced Senescence in Liver Cells Promotes M2 Macrophage Polarization: Implications for Tyrosine Kinase Inhibitor-Associated Hepatotoxicity09:32

Drug-Induced Senescence in Liver Cells Promotes M2 Macrophage Polarization: Implications for Tyrosine Kinase Inhibitor-Associated Hepatotoxicity

Published on: October 17, 2025

Related Concept Videos

PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a rapamycin-insensitive companion...
Glucagon-like Receptor Agonists01:24

Glucagon-like Receptor Agonists

Incretins include glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which stimulate insulin secretion post-meals. In type 2 diabetes, GIP's efficacy is reduced, making GLP-1 a viable drug target. GIP originates from preproGIP.
GLP-1, when administered in high doses intravenously, triggers insulin secretion, inhibits glucagon release, slows gastric emptying, reduces food intake, and restores normal insulin secretion. However, its rapid inactivation by the...
cAMP-dependent Protein Kinase Pathways01:25

cAMP-dependent Protein Kinase Pathways

Cyclic Adenosine Monophosphate (cAMP) is an essential second messenger that activates protein kinase A (PKA) and regulates various biological processes. A single epinephrine molecule binds to GPCR and activates several heterotrimeric G proteins, each stimulating multiple adenylyl cyclase, amplifying the signal, and synthesizing large numbers of cAMP molecules. Small changes in cAMP concentration affect PKA activity. The binding of four cAMP molecules induces a conformational change in PKA,...
Transducer Mechanism: Enzyme-Linked Receptors01:27

Transducer Mechanism: Enzyme-Linked Receptors

Enzyme-linked receptors are cell-surface receptors acting as an enzyme or associating with an enzyme intracellularly. They make excellent drug targets. Drugs can bind to the extracellular ligand-binding domain or directly affect their enzymatic domain and alter their activity.
Major types that are helpful drug targets include:
GPCRs Regulate Adenylyl Cylase Activity01:09

GPCRs Regulate Adenylyl Cylase Activity

Some GPCRs transmit signals through adenylyl cyclase (AC), a transmembrane enzyme. AC helps synthesize second messenger cyclic adenosine monophosphate (cAMP). AC catalyzes cyclization reaction and converts ATP to cAMP by releasing a pyrophosphate. The pyrophosphate is further hydrolyzed to phosphate by the enzyme pyrophosphatase, which drives cAMP synthesis to completion. However, cAMP is rapidly degraded to 5′ AMP by the enzymes phosphodiesterase (PDE), preventing overstimulation of cells.
Two...
Pharmacogenomics: Identification of New Drug Targets01:29

Pharmacogenomics: Identification of New Drug Targets

Advances in genomics have profoundly influenced drug discovery by increasing both the speed and accuracy of pharmaceutical development. Pharmacogenomics, which examines how genetic variation influences drug response, facilitates the identification of novel therapeutic targets and enables patient stratification for personalized treatment. These strategies contribute to improved drug efficacy, minimized adverse effects, and more efficient clinical trial design.Mapping genetic differences...