Abstract
Background: HER2-positive breast cancer, known for its heterogeneity and complex molecular mechanisms, poses a significant therapeutic challenge. Lidocaine, a widely used local anesthetic, has recently been identified as a potential anticancer agent. This study investigates the effects of lidocaine on HER2-positive breast cancer proliferation and the underlying mechanisms. Methods: The effects of lidocaine on cell proliferation, cell cycle distribution, and O-GlcNAcylation levels in AU565 and BT474 cells were assessed using CCK-8 assays, EdU incorporation assays, flow cytometry, and western blot analysis. Furthermore, the interaction between lidocaine and OGT was examined using molecular docking and co-immunoprecipitation (co-IP) experiments. Results: Lidocaine was found to significantly inhibit cell viability and proliferation in AU565 and BT474 cells, inducing G0/G1 cell cycle arrest. Mechanistically, lidocaine was observed to downregulate O-GlcNAc transferase (OGT), consequently reducing global O-GlcNAcylation levels. We further demonstrated that OGT interacts with and stabilizes CCNL1 via O-GlcNAcylation, and this interaction is critical for CCNL1-mediated cancer cell proliferation. Notably, rescue experiments revealed that the overexpression of either OGT or CCNL1 could partially reverse the suppressive effects of lidocaine. Conclusions: In conclusion, this study reveals a novel mechanism by which lidocaine inhibits HER2-positive breast cancer cell proliferation by targeting the OGT-CCNL1 axis, highlighting a potential therapeutic avenue for HER2-positive breast cancer.