Fiorillo, M, Scatena, C, Naccarato, AG, Sotgia, F 
ORCID: https://orcid.org/0000-0003-2826-4529 and Lisanti, MP ORCID: https://orcid.org/0000-0003-2034-1382
2021,
'Bedaquiline, an FDA-approved drug, inhibits mitochondrial ATP production and metastasis in vivo, by targeting the gamma subunit (ATP5F1C) of the ATP synthase'
, Cell Death and Differentiation, 28 (9)
, pp. 2797-2817.
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Abstract
Here, we provide evidence that high ATP production by the mitochondrial ATP-synthase is a new therapeutic target for anticancer therapy, especially for preventing tumor progression. More specifically, we isolated a subpopulation of ATP-high cancer cells which are phenotypically aggressive and demonstrate increases in proliferation, stemness, anchorage-independence, cell migration, invasion and multi-drug resistance, as well as high antioxidant capacity. Clinically, these findings have important implications for understanding treatment failure and cancer cell dormancy. Using bioinformatic analysis of patient samples, we defined a mitochondrial-related gene signature for metastasis, which features the gamma-subunit of the mitochondrial ATP-synthase (ATP5F1C). The relationship between ATP5F1C protein expression and metastasis was indeed confirmed by immunohistochemistry. Next, we used MDA-MB-231 cells as a model system to functionally validate these findings. Importantly, ATP-high MDA-MB-231 cells showed a nearly fivefold increase in metastatic capacity in vivo. Consistent with these observations, ATP-high cells overexpressed (i) components of mitochondrial complexes I-V, including ATP5F1C, and (ii) markers associated with circulating tumor cells (CTCs) and metastasis, such as EpCAM and VCAM1. Knockdown of ATP5F1C expression significantly reduced ATP-production, anchorage-independent growth, and cell migration, as predicted. Similarly, therapeutic administration of the FDA-approved drug, Bedaquiline, downregulated ATP5F1C expression in vitro and prevented spontaneous metastasis in vivo. In contrast, Bedaquiline had no effect on the growth of non-tumorigenic mammary epithelial cells (MCF10A) or primary tumors in vivo. Taken together, our results suggest that mitochondrial ATP depletion is a new therapeutic strategy for metastasis prophylaxis, to avoid treatment failure. In summary, we conclude that mitochondrial ATP5F1C is a promising new biomarker and molecular target for future drug development, for the prevention of metastatic disease progression.
| Item Type: | Article |
|---|---|
| Additional Information: | ** From PubMed via Jisc Publications Router **Journal IDs: eissn 1476-5403 **Article IDs: pubmed: 33986463; pii: 10.1038/s41418-021-00788-x **History: accepted 15-04-2021; revised 09-04-2021; submitted 23-10-2020 |
| Schools: | Schools > School of Environment and Life Sciences |
| Journal or Publication Title: | Cell Death and Differentiation |
| Publisher: | Springer Nature Publishing Group |
| ISSN: | 1350-9047 |
| Related URLs: | |
| SWORD Depositor: | Publications Router |
| Depositing User: | Publications Router |
| Date Deposited: | 28 May 2021 08:36 |
| Last Modified: | 15 Feb 2022 17:37 |
| URI: | https://usir.salford.ac.uk/id/eprint/60419 |
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