High ATP Production Fuels Cancer Drug Resistance and Metastasis: Implications for Mitochondrial ATP Depletion Therapy
Recently, we presented evidence that high mitochondrial ATP production is a new therapeutic target for cancer treatment. Using ATP as a biomarker, we isolated the “metabolically fittest” cancer cells from the total cell population. Importantly, ATP-high cancer cells were phenotypically the most aggr...
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| Vydáno v: | Frontiers in oncology Ročník 11; s. 740720 |
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| Hlavní autoři: | , , , |
| Médium: | Journal Article |
| Jazyk: | angličtina |
| Vydáno: |
Frontiers Media S.A
15.10.2021
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| Témata: | |
| ISSN: | 2234-943X, 2234-943X |
| On-line přístup: | Získat plný text |
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| Shrnutí: | Recently, we presented evidence that high mitochondrial ATP production is a new therapeutic target for cancer treatment. Using ATP as a biomarker, we isolated the “metabolically fittest” cancer cells from the total cell population. Importantly, ATP-high cancer cells were phenotypically the most aggressive, with enhanced stem-like properties, showing multi-drug resistance and an increased capacity for cell migration, invasion and spontaneous metastasis. In support of these observations, ATP-high cells demonstrated the up-regulation of both mitochondrial proteins and other protein biomarkers, specifically associated with stemness and metastasis. Therefore, we propose that the “energetically fittest” cancer cells would be better able to resist the selection pressure provided by i) a hostile micro-environment and/or ii) conventional chemotherapy, allowing them to be
naturally-selected
for survival, based on their high ATP content, ultimately driving tumor recurrence and distant metastasis. In accordance with this energetic hypothesis, ATP-high MDA-MB-231 breast cancer cells showed a dramatic increase in their ability to metastasize in a pre-clinical model
in vivo
. Conversely, metastasis was largely prevented by treatment with an FDA-approved drug (Bedaquiline), which binds to and inhibits the mitochondrial ATP-synthase, leading to ATP depletion. Clinically, these new therapeutic approaches could have important implications for preventing treatment failure and avoiding cancer cell dormancy, by employing ATP-depletion therapy, to target even the fittest cancer cells. |
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| Bibliografie: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 ObjectType-Review-3 content type line 23 Edited by: Chris Albanese, Georgetown University, United States This article was submitted to Cancer Metabolism, a section of the journal Frontiers in Oncology Reviewed by: Pau B. Esparza-Moltó, Salk Institute for Biological Studies, United States; Sujit Kumar Bhutia, National Institute of Technology Rourkela, India; Stefano Falone, University of L’Aquila, Italy |
| ISSN: | 2234-943X 2234-943X |
| DOI: | 10.3389/fonc.2021.740720 |