Aquaporin 1 promotes sensitivity of anthracycline chemotherapy in breast cancer by inhibiting β-catenin degradation to enhance TopoIIα activity

• Published in: Cell death and differentiation Vol. 28; no. 1; pp. 382 - 400
• Main Authors: Chong, Wei, Zhang, Huikun, Guo, Zhifang, Yang, Limin, Shao, Ying, Liu, Xiaoli, Zhao, Yawen, Wang, Zhe, Zhang, Ming, Guo, Caixia, Fu, Li, Ma, Yongjie, Gu, Feng
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-01-2021; Nature Publishing Group
• Subjects: 13; 13/51; 13/95; 14/19; 38/61; 38/77; 38/91; 45/23; 64/60; 692/53/2423; 692/699/67/1857; Animals; Anthracycline; Anthracyclines - therapeutic use; Antibiotics, Antineoplastic - therapeutic use; Apoptosis; Aquaporin 1; Aquaporin 1 - metabolism; beta Catenin - metabolism; Biochemistry; Biomedical and Life Sciences; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Cell Biology; Cell Cycle Analysis; Chemotherapy; Cytoplasm; Female; Glycogen; Glycogen synthase kinase 3; Humans; Kinases; Life Sciences; Mice; Mice, Inbred BALB C; Mice, Nude; Nuclear transport; Patients; Prognosis; Stem Cells; Xenograft Model Antitumor Assays; β-Catenin
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/s41418-020-00607-9

Anthracyclines are a class of conventional and commonly used frontline chemotherapy drugs to treat breast cancer. However, the anthracycline-based regimens can only reduce breast cancer mortality by 20–30%. Furthermore, there is no appropriate biomarker for predicting responses to this kind of chemotherapy currently. Here we report our findings that may fill this gap by showing the AQP1 (Aquaporin1) protein as a potential response predictor in the anthracycline chemotherapy. We showed that breast cancer patients with a high level of AQP1 expression who underwent the anthracycline treatment had a better clinical outcome relative to those with a low level of AQP1 expression. In the exploration of the underlying mechanisms, we found that the AQP1 and glycogen synthase kinase-3β (GSK3β) competitively interacted with the 12 armadillo repeats of β-catenin, followed by the inhibition of the β-catenin degradation that led to β-catenin’s accumulation in the cytoplasm and nuclear translocation. The nuclear β-catenin interacted with TopoIIα and enhanced TopoIIα’s activity, which resulted in a high sensitivity of breast cancer cells to anthracyclines. We also found, the miR-320a-3p can attenuate the anthracycline’s chemosensitivity by inhibiting the AQP1 expression. Taken together, our findings suggest the efficacy of AQP1 as a response predictor in the anthracycline chemotherapy. The application of our study includes, but is not limited to, facilitating screening of the most appropriate breast cancer patients (who have a high AQP1 expression) for better anthracycline chemotherapy and improved prognosis purposes.