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.
Keywords: Breast cancer; Degradation; Drug resistance; Estrogen receptor alpha; SVCT2; XIAP.
© 2025. The Author(s).