Estrogen receptor α regulates SVCT2 protein level in human breast cancer cells
Abstract The solute carrier (SLC) protein family, traditionally recognized for transporting molecules across cell membranes, is gaining attention for its broader roles, including signaling. Among SLC proteins, the ascorbate transporter SVCT2 remains poorly understood, particularly in relation to est...
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Nature Portfolio
2025-07-01
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| Online Access: | https://doi.org/10.1038/s41598-025-11758-5 |
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| author | Soon Young Jang Eunbi Hong Yebin Jo Jiyun Kim Jong-Ho Kim Yuran Na Chang-Hwan Yeom Yoon Jung Yang Emanuela Jacchetti Manuela Teresa Raimondi Seyeon Park |
| author_facet | Soon Young Jang Eunbi Hong Yebin Jo Jiyun Kim Jong-Ho Kim Yuran Na Chang-Hwan Yeom Yoon Jung Yang Emanuela Jacchetti Manuela Teresa Raimondi Seyeon Park |
| author_sort | Soon Young Jang |
| collection | DOAJ |
| description | Abstract The solute carrier (SLC) protein family, traditionally recognized for transporting molecules across cell membranes, is gaining attention for its broader roles, including signaling. Among SLC proteins, the ascorbate transporter SVCT2 remains poorly understood, particularly in relation to estrogen receptor alpha (ERα), a key regulator in breast cancer cells. Here, we investigate how ERα regulates SVCT2 and its implications for chemoresistance. Our results demonstrate that ERα knockdown significantly reduces SVCT2 protein levels, impairing cellular ascorbic acid uptake. Mechanistically, ERα directly interacts with SVCT2. We show that X-linked inhibitor of apoptosis protein (XIAP), an E3 ubiquitin ligase, targets SVCT2 for ubiquitination and subsequent proteasomal degradation in ERα-deficient conditions. Notably, silencing XIAP restored SVCT2 stability, underscoring its regulatory role. Functionally, ERα or SVCT2 knockdown decreases doxorubicin-induced cytotoxicity, accompanied by increased expression of ATP-binding cassette (ABC) transporter genes, which mediate drug efflux and contribute to chemoresistance. These findings uncover a novel regulatory axis between ERα and SVCT2, mediated by XIAP, and establish SVCT2 as a critical factor in maintaining cellular ascorbic acid levels and drug sensitivity. Targeting XIAP or modulating SVCT2 may represent promising therapeutic strategies for overcoming resistance in ERα-positive breast cancer. This study advances our understanding of the interplay between nutrient transport and cancer therapy, offering new avenues for intervention. |
| format | Article |
| id | doaj-art-e837e8659e8b459d9d4fb0ce9d58dfa9 |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-e837e8659e8b459d9d4fb0ce9d58dfa92025-08-20T03:46:04ZengNature PortfolioScientific Reports2045-23222025-07-0115111710.1038/s41598-025-11758-5Estrogen receptor α regulates SVCT2 protein level in human breast cancer cellsSoon Young Jang0Eunbi Hong1Yebin Jo2Jiyun Kim3Jong-Ho Kim4Yuran Na5Chang-Hwan Yeom6Yoon Jung Yang7Emanuela Jacchetti8Manuela Teresa Raimondi9Seyeon Park10Department of Applied Chemistry, Dongduk Women’s UniversityDepartment of Applied Chemistry, Dongduk Women’s UniversityDepartment of Applied Chemistry, Dongduk Women’s UniversityDepartment of Applied Chemistry, Dongduk Women’s UniversityDepartment of Pharmacy, Graduate School, Kyung Hee UniversityRappeler Company (4F)Rappeler Company (4F)Department of Food and Nutrition, Dongduk Women’s UniversityDepartment of Chemistry, Materials and Chemical Engineering ‘Giulio Natta, Politecnico Di MilanoDepartment of Chemistry, Materials and Chemical Engineering ‘Giulio Natta, Politecnico Di MilanoDepartment of Applied Chemistry, Dongduk Women’s UniversityAbstract The solute carrier (SLC) protein family, traditionally recognized for transporting molecules across cell membranes, is gaining attention for its broader roles, including signaling. Among SLC proteins, the ascorbate transporter SVCT2 remains poorly understood, particularly in relation to estrogen receptor alpha (ERα), a key regulator in breast cancer cells. Here, we investigate how ERα regulates SVCT2 and its implications for chemoresistance. Our results demonstrate that ERα knockdown significantly reduces SVCT2 protein levels, impairing cellular ascorbic acid uptake. Mechanistically, ERα directly interacts with SVCT2. We show that X-linked inhibitor of apoptosis protein (XIAP), an E3 ubiquitin ligase, targets SVCT2 for ubiquitination and subsequent proteasomal degradation in ERα-deficient conditions. Notably, silencing XIAP restored SVCT2 stability, underscoring its regulatory role. Functionally, ERα or SVCT2 knockdown decreases doxorubicin-induced cytotoxicity, accompanied by increased expression of ATP-binding cassette (ABC) transporter genes, which mediate drug efflux and contribute to chemoresistance. These findings uncover a novel regulatory axis between ERα and SVCT2, mediated by XIAP, and establish SVCT2 as a critical factor in maintaining cellular ascorbic acid levels and drug sensitivity. Targeting XIAP or modulating SVCT2 may represent promising therapeutic strategies for overcoming resistance in ERα-positive breast cancer. This study advances our understanding of the interplay between nutrient transport and cancer therapy, offering new avenues for intervention.https://doi.org/10.1038/s41598-025-11758-5SVCT2Estrogen receptor alphaDegradationXIAPDrug resistanceBreast cancer |
| spellingShingle | Soon Young Jang Eunbi Hong Yebin Jo Jiyun Kim Jong-Ho Kim Yuran Na Chang-Hwan Yeom Yoon Jung Yang Emanuela Jacchetti Manuela Teresa Raimondi Seyeon Park Estrogen receptor α regulates SVCT2 protein level in human breast cancer cells Scientific Reports SVCT2 Estrogen receptor alpha Degradation XIAP Drug resistance Breast cancer |
| title | Estrogen receptor α regulates SVCT2 protein level in human breast cancer cells |
| title_full | Estrogen receptor α regulates SVCT2 protein level in human breast cancer cells |
| title_fullStr | Estrogen receptor α regulates SVCT2 protein level in human breast cancer cells |
| title_full_unstemmed | Estrogen receptor α regulates SVCT2 protein level in human breast cancer cells |
| title_short | Estrogen receptor α regulates SVCT2 protein level in human breast cancer cells |
| title_sort | estrogen receptor α regulates svct2 protein level in human breast cancer cells |
| topic | SVCT2 Estrogen receptor alpha Degradation XIAP Drug resistance Breast cancer |
| url | https://doi.org/10.1038/s41598-025-11758-5 |
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