Metadherin inhibits triple-negative breast cancer chemosensitivity to paclitaxel via activation of the AKT/GSK-3β signaling pathway

Abstract

Abstract Triple-negative breast cancer (TNBC) has an aggressive clinical course and paclitaxel (PTX)-based chemotherapy is still its main therapeutic drug. Metadherin (MTDH) acts as an oncogene by regulating cellular transformation, proliferation, invasion, metastasis, chemoresistance, and angiogenesis. This study aimed to investigate whether TNBC chemosensitivity to PTX was related to the MTDH/AKT/GSK-3β pathway. We found that higher expression of MTDH or AKT showed poorer DFS and lower Miller–Payne grad. MTDH promoted cell proliferation and increased p-AKT and pGSK3β expression in TNBC cells. Notably, suppression of AKT terminated MTDH overexpression-induced cell proliferation and apoptosis. MTDH knockdown or AKT inhibitor MK2206 could reduce the p-AKT and pGSK3β ratio, reduced cell viability and proliferation, increased cell apoptosis, and increased chemosensitivity to PTX. In vivo, xenograft tumor of an MTDH knockdown + MK2206 group treated with PTX was the smallest compared to other groups. These results showed that MTDH inhibits TNBC chemosensitivity to PTX via activating AKT/GSK-3β signaling pathway, while inhibiting both MTDH and AKT can significantly increase the sensitivity.