title: Inhibiting the MNK-eIF4E-β-catenin axis increases the responsiveness of aggressive breast cancer cells to chemotherapy.
abstract: Advanced breast cancer (eg. stage IV) is resistant to chemotherapy. In this work, we identified potentially druggable targets that are critically involved in chemoresistance. We showed that eIF4E is highly phosphorylated at serine 209 in breast cancer patients in response to chemotherapy, which significantly correlated with poorer clinical responses and outcomes. Depletion of eIF4E enhanced the anti-proliferative and pro-apoptotic effects of chemotherapeutic drugs in breast cancer cells. Chemotherapy activated the Wnt/β-catenin signaling in an eIF4E-dependent manner. However, MNK inhibitors prevented chemotherapeutic drug-induced eIF4E phosphorylation and β-catenin activation, which enhanced the breast cancer cell response to chemotherapy in vitro and in vivo. These findings indicate MNK-eIF4E-β-catenin is an activator of the breast cancer cell response to chemotherapy and highlights the therapeutic value of inhibiting MNK to overcome chemoresistance in breast cancer.
authors.affiliation: Department of Oncology, Sanya People's Hospital, Sanya 572000, China.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Oncology, Sanya People's Hospital, Sanya 572000, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Special Care Unit, Sanya People's Hospital, Sanya 572000, China.
authors.forename: Miao
authors.initials: M
authors.lastname: Qu
authors.affiliation: Department of Oncology, Sanya People's Hospital, Sanya 572000, China.
authors.forename: Hongxing
authors.initials: H
authors.lastname: Wan
authors.affiliation: Department of Pharmacy, Sanya People's Hospital, Sanya 572000, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Cai
authors.affiliation: Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000073840:Copper-Transporting ATPases / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D039561:Eukaryotic Initiation Factor-4E / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D009154:Mutation; D010766:Phosphorylation; D015398:Signal Transduction / Q000187:drug effects*; D016896:Treatment Outcome; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D039561:Eukaryotic Initiation Factor-4E; D051176:beta Catenin; C081184:ATP7A protein, human; D000073840:Copper-Transporting ATPases
keywords: MNK; breast cancer; chemoresistance; eIF4E; β-catenin