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FoxO3a Drives the Metabolic Reprogramming in Tamoxifen-Resistant Breast Cancer Cells Restoring Tamoxifen Sensitivity

Fiorillo, Marco; Ricci, Elena; Fava, Mariarosa; Longobucco, Camilla; Sotgia, Federica; Rizza, Pietro; Lanzino, Marilena; Bonofiglio, Daniela; Conforti, Francesca Luisa; Catalano, Stefania; Barone, Ines; Morelli, Catia; Aquila, Saveria; Lisanti, Michael P.; Sisci, Diego

FoxO3a Drives the Metabolic Reprogramming in Tamoxifen-Resistant Breast Cancer Cells Restoring Tamoxifen Sensitivity Thumbnail


Authors

Marco Fiorillo

Elena Ricci

Mariarosa Fava

Camilla Longobucco

Pietro Rizza

Marilena Lanzino

Daniela Bonofiglio

Francesca Luisa Conforti

Stefania Catalano

Ines Barone

Catia Morelli

Saveria Aquila

Michael P. Lisanti

Diego Sisci



Abstract

Tamoxifen-resistant breast cancer cells (TamR-BCCs) are characterized by an enhanced metabolic phenotype compared to tamoxifen-sensitive cells. FoxO3a is an important modulator of cell metabolism, and its deregulation has been involved in the acquisition of tamoxifen resistance. Therefore, tetracycline-inducible FoxO3a was overexpressed in TamR-BCCs (TamR/TetOn-AAA), which, together with their control cell line (TamR/TetOn-V), were subjected to seahorse metabolic assays and proteomic analysis. FoxO3a was able to counteract the increased oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) observed in TamR by reducing their energetic activity and glycolytic rate. FoxO3a caused glucose accumulation, very likely by reducing LDH activity and mitigated TamR biosynthetic needs by reducing G6PDH activity and hindering NADPH production via the pentose phosphate pathway (PPP). Proteomic analysis revealed a FoxO3a-dependent marked decrease in the expression of LDH as well as of several enzymes involved in carbohydrate metabolism (e.g., Aldolase A, LDHA and phosphofructokinase) and the analysis of cBioPortal datasets of BC patients evidenced a significant inverse correlation of these proteins and FoxO3a. Interestingly, FoxO3a also increased mitochondrial biogenesis despite reducing mitochondrial functionality by triggering ROS production. Based on these findings, FoxO3a inducing/activating drugs could represent promising tools to be exploited in the management of patients who are refractory to antiestrogen therapy.

Citation

Fiorillo, M., Ricci, E., Fava, M., Longobucco, C., Sotgia, F., Rizza, P., …Sisci, D. (in press). FoxO3a Drives the Metabolic Reprogramming in Tamoxifen-Resistant Breast Cancer Cells Restoring Tamoxifen Sensitivity. Cells, 12(24), 2777. https://doi.org/10.3390/cells12242777

Journal Article Type Article
Acceptance Date Nov 29, 2023
Online Publication Date Dec 6, 2023
Deposit Date Jan 9, 2024
Publicly Available Date Jan 9, 2024
Journal Cells
Publisher MDPI
Peer Reviewed Peer Reviewed
Volume 12
Issue 24
Pages 2777
DOI https://doi.org/10.3390/cells12242777
Keywords General Medicine