Jang Soon Young, Hong Eunbi, Jo Yebin, Kim Jiyun, Kim Jong-Ho, Na Yuran, Yeom Chang-Hwan, Yang Yoon Jung, Jacchetti Emanuela, Raimondi Manuela Teresa, Park Seyeon
Department of Applied Chemistry, Dongduk Women's University, 60 Hwarang-Ro 13-Gil, Seongbuk-Gu, Seoul, Korea.
Rappeler Company (4F), 39 LS-Ro 116 Beon-Gil, Dongan-Gu, Anyang, Gyeonggi-Do, Korea.
Sci Rep. 2025 Jul 29;15(1):27629. doi: 10.1038/s41598-025-11758-5.
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.
溶质载体（SLC）蛋白家族传统上因能跨细胞膜转运分子而为人所知，如今其更广泛的作用（包括信号传导）正受到关注。在SLC蛋白中，抗坏血酸转运体SVCT2仍未被充分了解，尤其是在与雌激素受体α（ERα）（乳腺癌细胞中的关键调节因子）相关方面。在此，我们研究ERα如何调节SVCT2及其对化疗耐药性的影响。我们的结果表明，敲低ERα会显著降低SVCT2蛋白水平，损害细胞对抗坏血酸的摄取。从机制上讲，ERα直接与SVCT2相互作用。我们发现，X连锁凋亡抑制蛋白（XIAP）（一种E3泛素连接酶）在ERα缺陷条件下靶向SVCT2进行泛素化及随后的蛋白酶体降解。值得注意的是，沉默XIAP可恢复SVCT2的稳定性，强调了其调节作用。在功能上，敲低ERα或SVCT2会降低阿霉素诱导的细胞毒性，同时伴随着ATP结合盒（ABC）转运体基因表达增加，这些基因介导药物外排并导致化疗耐药。这些发现揭示了由XIAP介导的ERα与SVCT2之间的新型调节轴，并确定SVCT2是维持细胞内抗坏血酸水平和药物敏感性的关键因素。靶向XIAP或调节SVCT2可能是克服ERα阳性乳腺癌耐药的有前景的治疗策略。这项研究推进了我们对营养物质转运与癌症治疗之间相互作用的理解，为干预提供了新途径。
