ATP6V0D2 drives triple-negative breast cancer progression and inhibits cisplatin sensitivity by promoting PHLPP2 lysosomal degradation.

ABSTRACT: Triple-negative breast cancer (TNBC) faces therapeutic challenges due to limited treatment options and frequent chemoresistance. In this study, we identify ATP6V0D2 as a key factor upregulated in TNBC, where its expression correlates with poor prognosis. Transcriptomic and functional analyses linked ATP6V0D2 to PI3K/AKT signaling and platinum drug resistance. Mechanistically, ATP6V0D2 enhanced lysosomal function to promote degradation of the tumor suppressor PHLPP2, thereby sustaining AKT phosphorylation. Functional assays showed that ATP6V0D2 knockdown increased cisplatin sensitivity both in vitro and in vivo. Furthermore, pharmacological inhibition of V-ATPase with bafilomycinA1 sensitized TNBC patient-derived organoids to cisplatin. Clinically, our analysis of 91 TNBC pati

SUBMITTER: Zhang J 

PROVIDER: S-EPMC12648496 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature