Biguanides antithetically regulate tumor properties by the dose-dependent mitochondrial reprogramming-driven c-Src pathway
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.
Authors
- Benny Abraham Kaipparettu (ORCID: https://orcid.org/0000-0003-3444-4307)
- Nagireddy Putluri (ORCID: https://orcid.org/0000-0003-4488-7400)
- Meron Ghidey
- Joyce V. Lee (ORCID: https://orcid.org/0000-0003-2620-555X)
- Kuldeep S. Attri (ORCID: https://orcid.org/0000-0002-0668-5245)
- Seung Yeop Han (ORCID: https://orcid.org/0000-0001-8837-4522)
- Sukjin Yang (ORCID: https://orcid.org/0000-0001-6160-8528)
- Vasanta Putluri (ORCID: https://orcid.org/0000-0001-7943-2209)
- Somik Chatterjee (ORCID: https://orcid.org/0000-0001-6869-4019)
- Diego A. Pedroza (ORCID: https://orcid.org/0000-0002-7355-2952)
- José N. Onuchic (ORCID: https://orcid.org/0000-0002-9448-0388)
- Caitlin M. Davis (ORCID: https://orcid.org/0000-0003-4340-4577)
- Michael T. Lewis (ORCID: https://orcid.org/0000-0002-6330-4007)
- Songyeon Ahn (ORCID: https://orcid.org/0000-0001-8078-5765)
- Lacey E. Dobrolecki (ORCID: https://orcid.org/0000-0001-6839-629X)
- Debasmita Dutta (ORCID: https://orcid.org/0000-0003-0235-4649)
- K.H. Jung
- Chad J. Creighton (ORCID: https://orcid.org/0000-0002-6090-703X)
- Andrei Goga (ORCID: https://orcid.org/0000-0001-9127-0986)
- Dongya Jia (ORCID: https://orcid.org/0000-0002-6307-8580)
- Tagari Samanta (ORCID: https://orcid.org/0000-0003-2825-6801)
- Divya Murthy (ORCID: https://orcid.org/0000-0001-6492-1894)
- Jeffrey M. Rosen (ORCID: https://orcid.org/0000-0002-6637-844X)
- Shuting Li (ORCID: https://orcid.org/0000-0002-7670-689X)
- Jun Hyoung Park
- Abha Tiwari
Institutions
- University of California, San Francisco (US)
- Baylor College of Medicine (US)
- Center for Theoretical Biological Physics (US)
- Baylor Genetics (US)
- Rice University (US)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2025-02-01
- DOI
- https://doi.org/10.1016/j.xcrm.2025.101941
- Citations
- 9
- Primary Topic
- Cancer, Hypoxia, and Metabolism
- Type
- article
- Field-Weighted Citation Impact
- 8.43
Funders
- National Science Foundation
- U.S. Department of Defense
- Welch Foundation
- Cancer Prevention and Research Institute of Texas
- Mark Foundation For Cancer Research
- National Institutes of Health
- National Cancer Institute