Skip to main content

Research Repository

Advanced Search

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

Fiorillo, M; Ozsvari, B; Sotgia, F; Lisanti, MP

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


Authors

M Fiorillo

B Ozsvari



Contributors

C Albanese
Editor

SK Bhutia
Other

S Falone
Other

PB Esparza-Moltó
Other

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.

Citation

Fiorillo, M., Ozsvari, B., Sotgia, F., & Lisanti, M. (2021). High ATP production fuels cancer drug resistance and metastasis : implications for mitochondrial ATP depletion therapy. Frontiers in Oncology, 11, 740720. https://doi.org/10.3389/fonc.2021.740720

Journal Article Type Article
Acceptance Date Sep 7, 2021
Online Publication Date Oct 15, 2021
Publication Date Oct 15, 2021
Deposit Date Nov 2, 2021
Publicly Available Date Nov 2, 2021
Journal Frontiers in Oncology
Publisher Frontiers Media
Volume 11
Pages 740720
DOI https://doi.org/10.3389/fonc.2021.740720
Publisher URL https://doi.org/10.3389/fonc.2021.740720
Related Public URLs https://www.frontiersin.org/journals/451
Additional Information 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

Files






You might also like



Downloadable Citations