FoxO3a Drives the Metabolic Reprogramming in Tamoxifen-Resistant Breast Cancer Cells Restoring Tamoxifen Sensitivity
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, tetracycl...
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MDPI AG
2023-12-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/12/24/2777 |
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| author | Marco Fiorillo Elena Ricci Mariarosa Fava Camilla Longobucco Federica Sotgia Pietro Rizza Marilena Lanzino Daniela Bonofiglio Francesca Luisa Conforti Stefania Catalano Ines Barone Catia Morelli Saveria Aquila Michael P. Lisanti Diego Sisci |
| author_facet | Marco Fiorillo Elena Ricci Mariarosa Fava Camilla Longobucco Federica Sotgia Pietro Rizza Marilena Lanzino Daniela Bonofiglio Francesca Luisa Conforti Stefania Catalano Ines Barone Catia Morelli Saveria Aquila Michael P. Lisanti Diego Sisci |
| author_sort | Marco Fiorillo |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-08T20:54:56Z |
| format | Article |
| id | doaj.art-a318d65fff1b4bb8820e166359d731bb |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-08T20:54:56Z |
| publishDate | 2023-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-a318d65fff1b4bb8820e166359d731bb2023-12-22T13:59:33ZengMDPI AGCells2073-44092023-12-011224277710.3390/cells12242777FoxO3a Drives the Metabolic Reprogramming in Tamoxifen-Resistant Breast Cancer Cells Restoring Tamoxifen SensitivityMarco Fiorillo0Elena Ricci1Mariarosa Fava2Camilla Longobucco3Federica Sotgia4Pietro Rizza5Marilena Lanzino6Daniela Bonofiglio7Francesca Luisa Conforti8Stefania Catalano9Ines Barone10Catia Morelli11Saveria Aquila12Michael P. Lisanti13Diego Sisci14Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, ItalyDepartment of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, ItalyDepartment of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, ItalyDepartment of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, ItalyTranslational Medicine, School of Environment and Life Sciences, Biomedical Research Centre (BRC), University of Salford, Greater Manchester M5 4WT, UKDepartment of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, ItalyDepartment of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, ItalyDepartment of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, ItalyDepartment of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, ItalyDepartment of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, ItalyDepartment of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, ItalyDepartment of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, ItalyDepartment of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, ItalyTranslational Medicine, School of Environment and Life Sciences, Biomedical Research Centre (BRC), University of Salford, Greater Manchester M5 4WT, UKDepartment of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, ItalyTamoxifen-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.https://www.mdpi.com/2073-4409/12/24/2777FoxO3atamoxifen resistancebreast cancerglycolysiscancer metabolism |
| spellingShingle | Marco Fiorillo Elena Ricci Mariarosa Fava Camilla Longobucco Federica Sotgia Pietro Rizza Marilena Lanzino Daniela Bonofiglio Francesca Luisa Conforti Stefania Catalano Ines Barone Catia Morelli Saveria Aquila Michael P. Lisanti Diego Sisci FoxO3a Drives the Metabolic Reprogramming in Tamoxifen-Resistant Breast Cancer Cells Restoring Tamoxifen Sensitivity Cells FoxO3a tamoxifen resistance breast cancer glycolysis cancer metabolism |
| title | FoxO3a Drives the Metabolic Reprogramming in Tamoxifen-Resistant Breast Cancer Cells Restoring Tamoxifen Sensitivity |
| title_full | FoxO3a Drives the Metabolic Reprogramming in Tamoxifen-Resistant Breast Cancer Cells Restoring Tamoxifen Sensitivity |
| title_fullStr | FoxO3a Drives the Metabolic Reprogramming in Tamoxifen-Resistant Breast Cancer Cells Restoring Tamoxifen Sensitivity |
| title_full_unstemmed | FoxO3a Drives the Metabolic Reprogramming in Tamoxifen-Resistant Breast Cancer Cells Restoring Tamoxifen Sensitivity |
| title_short | FoxO3a Drives the Metabolic Reprogramming in Tamoxifen-Resistant Breast Cancer Cells Restoring Tamoxifen Sensitivity |
| title_sort | foxo3a drives the metabolic reprogramming in tamoxifen resistant breast cancer cells restoring tamoxifen sensitivity |
| topic | FoxO3a tamoxifen resistance breast cancer glycolysis cancer metabolism |
| url | https://www.mdpi.com/2073-4409/12/24/2777 |
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