Glucagon-like peptide-1 analogs activate AMP kinase leading to reversal of the Warburg metabolic switch in breast cancer cells.
Humans
Breast Neoplasms
/ drug therapy
Exenatide
/ pharmacology
Female
Liraglutide
/ pharmacology
Glucagon-Like Peptide 1
/ metabolism
Cell Line, Tumor
AMP-Activated Protein Kinases
/ metabolism
Signal Transduction
/ drug effects
Cell Survival
/ drug effects
Warburg Effect, Oncologic
/ drug effects
Cell Proliferation
/ drug effects
Venoms
/ pharmacology
Adenylate Kinase
/ metabolism
Peptides
/ pharmacology
AMPK
Breast Cancer
GLP-1 analogs
Metabolism
Viability
Journal
Medical oncology (Northwood, London, England)
ISSN: 1559-131X
Titre abrégé: Med Oncol
Pays: United States
ID NLM: 9435512
Informations de publication
Date de publication:
06 May 2024
06 May 2024
Historique:
received:
21
02
2024
accepted:
24
04
2024
medline:
6
5
2024
pubmed:
6
5
2024
entrez:
5
5
2024
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 38705935
doi: 10.1007/s12032-024-02390-w
pii: 10.1007/s12032-024-02390-w
doi:
Substances chimiques
Exenatide
9P1872D4OL
Liraglutide
839I73S42A
Glucagon-Like Peptide 1
89750-14-1
AMP-Activated Protein Kinases
EC 2.7.11.31
Venoms
0
Adenylate Kinase
EC 2.7.4.3
Peptides
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
138Informations de copyright
© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
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