High ATP production fuels cancer drug resistance and metastasis : implications for mitochondrial ATP depletion therapy

Fiorillo, M, Ozsvari, B, Sotgia, F ORCID: https://orcid.org/0000-0003-2826-4529 and Lisanti, MP ORCID: https://orcid.org/0000-0003-2034-1382 2021, 'High ATP production fuels cancer drug resistance and metastasis : implications for mitochondrial ATP depletion therapy' , Frontiers in Oncology, 11 , p. 740720.

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Abstract

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.

Item Type: Article
Contributors: Albanese, C (Editor), Bhutia, SK (Reviewer), Falone, S (Reviewer) and Esparza-Moltó, PB (Reviewer)
Additional Information: ** From Frontiers via Jisc Publications Router ** Licence for this article: http://creativecommons.org/licenses/by/4.0/ **Journal IDs: eissn 2234-943X **History: published_online 15-10-2021; accepted 07-09-2021; submitted 13-07-2021; collection 2021
Schools: Schools > School of Environment and Life Sciences > Biomedical Research Centre
Journal or Publication Title: Frontiers in Oncology
Publisher: Frontiers Media S.A.
ISSN: 2234-943X
Related URLs:
Funders: Lunella Biotech, Inc.
SWORD Depositor: Publications Router
Depositing User: Publications Router
Date Deposited: 02 Nov 2021 10:07
Last Modified: 02 Nov 2021 10:15
URI: http://usir.salford.ac.uk/id/eprint/62247

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