Language
English
Publication Date
2-18-2025
Journal
Cell Reports Metabolism
DOI
10.1016/j.xcrm.2025.101941
PMID
39933530
PMCID
PMC11866546
PubMedCentral® Posted Date
2-10-2025
PubMedCentral® Full Text Version
Post-print
Abstract
The biguanide metformin attenuates mitochondrial oxidation and is proposed as an anti-cancer therapy. However, recent clinical studies suggest increased proliferation and fatty acid β-oxidation (FAO) in a subgroup of patients with breast cancer (BC) after metformin therapy. Considering that FAO can activate Src kinase in aggressive triple-negative BC (TNBC), we postulate that low-dose biguanide-driven AMPK-ACC-FAO signaling may activate the Src pathway in TNBC. The low bioavailability of metformin in TNBC xenografts mimics metformin's in vitro low-dose effect. Pharmacological or genetic inhibition of FAO significantly enhances the anti-tumor properties of biguanides. Lower doses of biguanides induce and higher doses suppress Src signaling. Dasatinib and metformin synergistically inhibit TNBC patient-derived xenograft growth, but not in high-fat diet-fed mice. This combination also suppresses TNBC metastatic progression. A combination of biguanides with Src inhibitors provides synergy to target metastatic TNBC suffering with limited treatment options.
Keywords
Humans, Animals, Mitochondria, Signal Transduction, src-Family Kinases, Female, Metformin, Mice, Triple Negative Breast Neoplasms, Biguanides, Cell Line, Tumor, Dasatinib, Xenograft Model Antitumor Assays, Cell Proliferation, Antineoplastic Agents, Mice, Nude, Fatty Acids, AMP-Activated Protein Kinases, triple-negative breast cancer, fatty acid β-oxidation, mitochondria, metformin, Src kinase
Published Open-Access
yes
Recommended Citation
Park, Jun Hyoung; Jung, Kwang Hwa; Jia, Dongya; et al., "Biguanides Antithetically Regulate Tumor Properties by the Dose-Dependent Mitochondrial Reprogramming-Driven C-Src Pathway" (2025). Faculty and Staff Publications. 4394.
https://digitalcommons.library.tmc.edu/baylor_docs/4394