High ATP Production Fuels Cancer Drug Resistance and Metastasis: Implications for Mitochondrial ATP Depletion Therapy

Abstract

This study investigates the role of high mitochondrial ATP production in cancer progression, particularly its contribution to drug resistance and metastasis. By isolating ATP-high cancer cells, researchers found these cells to be more aggressive, exhibiting enhanced stem-like properties, multi-drug resistance, and increased metastatic potential. The study also explores the therapeutic potential of ATP-depletion strategies, highlighting the efficacy of Bedaquiline, an FDA-approved drug, in inhibiting mitochondrial ATP synthase and preventing metastasis in preclinical models.

Key Findings

• ATP-High Cancer Cells: Identified as the most aggressive subpopulation, with increased stemness, drug resistance, and metastatic capabilities.
• ATP5F1C as a Biomarker: The gamma subunit of mitochondrial ATP synthase (ATP5F1C) is upregulated in ATP-high cells and correlates with poor clinical outcomes.
• Bedaquiline Efficacy: Demonstrated to inhibit ATP synthase, reduce ATP production, and prevent spontaneous metastasis in vivo without affecting primary tumor growth.
• Therapeutic Implications: Targeting mitochondrial ATP production presents a promising strategy to combat drug resistance and metastasis in cancer therapy.

Methodology

Researchers utilized BioTracker ATP-Red 1 staining coupled with flow cytometry to isolate ATP-high and ATP-low subpopulations from cancer cell lines. Functional assays assessed proliferation, stemness, drug resistance, and metastatic potential. The effects of Bedaquiline on ATP production and metastasis were evaluated using in vitro assays and a chick embryo model.

Conclusion

The study underscores the significance of mitochondrial ATP production in driving cancer aggressiveness and resistance. By targeting ATP synthesis, particularly through agents like Bedaquiline, it may be possible to eliminate the most resilient cancer cell populations, thereby improving therapeutic outcomes and preventing metastasis.