Glucagon-like peptide-1 analogs activate AMP kinase leading to reversal of the Warburg metabolic switch in breast cancer cells

Hagai Ligumsky*, Sharon Amir, Tamar Arbel Rubinstein, Kate Guion, Tali Scherf, Avraham Karasik, Ido Wolf, Tami Rubinek

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Breast cancer (BC) is associated with type 2 diabetes mellitus (T2DM) and obesity. Glucagon-like peptide (GLP)-1 regulates post-prandial insulin secretion, satiety, and gastric emptying. Several GLP-1 analogs have been FDA-approved for the treatment of T2DM and obesity. Moreover, GLP-1 regulates various metabolic activities across different tissues by activating metabolic signaling pathways like adenosine monophosphate (AMP) activated protein kinase (AMPK), and AKT. Rewiring metabolic pathways is a recognized hallmark of cancer, regulated by several cancer-related pathways, including AKT and AMPK. As GLP-1 regulates AKT and AMPK, we hypothesized that it alters BC cells’ metabolism, thus inhibiting proliferation. The effect of the GLP-1 analogs exendin-4 (Ex4) and liraglutide on viability, AMPK signaling and metabolism of BC cell lines were assessed. Viability of BC cells was evaluated using colony formation and MTT/XTT assays. Activation of AMPK and related signaling effects were evaluated using western blot. Metabolism effects were measured for glucose, lactate and ATP. Exendin-4 and liraglutide activated AMPK in a cAMP-dependent manner. Blocking Ex4-induced activation of AMPK by inhibition of AMPK restored cell viability. Interestingly, Ex4 and liraglutide reduced the levels of glycolytic metabolites and decreased ATP production, suggesting that GLP-1 analogs impair glycolysis. Notably, inhibiting AMPK reversed the decline in ATP levels, highlighting the role of AMPK in this process. These results establish a novel signaling pathway for GLP-1 in BC cells through cAMP and AMPK modulation affecting proliferation and metabolism. This study suggests that GLP-1 analogs should be considered for diabetic patients with BC.

Original languageEnglish
Article number138
JournalMedical Oncology
Volume41
Issue number6
DOIs
StatePublished - Jun 2024

Funding

FundersFunder number
Morris Kahn Foundation

    Keywords

    • AMPK
    • Breast Cancer
    • GLP-1 analogs
    • Metabolism
    • Viability

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