Abstract
Metabolomic fingerprint of breast cancer cells treated with the antidiabetic drug metformin revealed a significant accumulation of 5-formimino-tetrahydrofolate, one of the tetrahydrofolate forms carrying activated one-carbon units that are essential for the de novo synthesis of purines and pyrimidines. De novo synthesis of glutathione, a folate-dependent pathway interconnected with one-carbon metabolism was concomitantly depleted in response to metformin. End-product reversal studies demonstrated that thymidine alone leads to a significant but incomplete protection from metformin's cytostatic effects. The addition of the substrate hypoxanthine for the purine salvage pathway produces major rightward shifts in metformin's growth inhibition curves. Metformin treatment failed to activate the DNA repair protein ATM kinase and the metabolic tumor suppressor AMPK when thymidine and hypoxanthine were present in the extracellular milieu. Our current findings suggest for the first time that metformin can function as an antifolate chemotherapeutic agent that induces the ATM/AMPK tumor suppressor axis secondarily following the alteration of the carbon flow through the folate-related one-carbon metabolic pathways.
Highlights
The exact site of action and molecular mechanism by which the anti-diabetic, biguanide metformin exerts its recently recognized anticancer activity is poorly understood and remains largely controversial [1,2,3,4,5]
We accumulate key arguments against the concept that metformin acts in vivo as a “mitochondrial poison” that inhibits complex I of the respiratory chain, which leads to an imbalance in the AMP-to-ATP ratio (AMP/ATP) ratio [13,14,15]
Metabolite level analysis demonstrates that onecarbon metabolism and the associated glutathione pathway are significantly altered in metformintreated breast cancer cells
Summary
The exact site of action and molecular mechanism by which the anti-diabetic, biguanide metformin exerts its recently recognized anticancer activity is poorly understood and remains largely controversial [1,2,3,4,5]. The ablation of adenylate kinase expression (the phosphotransferase that catalyzes the conversion of two ADP molecules to AMP and ATP) in muscle cells does not affect metformin’s activating effects on AMPK [24] This result suggests that any mechanism involving increased AMP formation driven by ATP turnover (and increased ADP formation) is improbable. In this complex scenario and as auspiciously suggested by Ouyang et al [24], “it is likely that the response of the cell to energy interruption is a distinct means of AMPK activation from the response to metformin”. At least in muscle cells, metformin may activate AMPK via the prevention of AMPD-catalyzed AMP breakdown
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
