title: AMPK activators suppress breast cancer cell growth by inhibiting DVL3-facilitated Wnt/β-catenin signaling pathway activity.
abstract: Adenosine monophosphate-activated protein kinase (AMPK) is a principal regulator of metabolism and the conservation of energy in cells, and protects them from exposure to various stressors. AMPK activators may exhibit therapeutic potential as suppressors of cell growth; however, the molecular mechanism underlying this phenomenon in various cancer cells remains to be fully elucidated. The present study investigated the effects of AMPK activators on breast cancer cell growth and specified the underlying molecular mechanism. In the present study, the AMPK activator metformin impaired breast cancer cell growth by reducing dishevelled segment polarity protein 3 (DVL3) and β‑catenin levels. Western blotting and immunohistochemistry demonstrated that DVL3 was recurrently upregulated in breast cancer cells that were not treated with metformin, and was significantly associated with enhanced levels of β‑catenin, c‑Myc and cyclin D1. Overexpression of DVL3 resulted in upregulation of β‑catenin and amplification of breast cancer cell growth, which confirmed that Wnt/β‑catenin activation via DVL3 is associated with breast cancer oncogenesis. To elucidate the underlying mechanism of these effects, the present study verified that metformin resulted in a downregulation of DVL3 and β‑catenin in a dose‑dependent manner, and induced phosphorylation of AMPK. Compound C is an AMPK inhibitor, which when administered alongside metformin, significantly abolished the effects of metformin on the reduction of DVL3 and activation of the phosphorylation of AMPK. Notably, the effects of metformin on the mRNA expression levels of DVL3 remain to be fully elucidated; however, a possible interaction with DVL3 at the post‑transcriptional level was observed. It has previously been suggested that the molecular mechanism underlying AMPK activator‑induced suppression of breast cancer cell growth involves an interaction with, and impairment of, DVL3 proteins. The results of the present study are of future clinical importance and advocate the use of metformin as a potential therapeutic agent against breast cancer.
authors.affiliation: Department of Breast Surgery, Nanchang University School of Medicine, Nanchang, Jiangxi 330006, P.R. China.
authors.forename: Yu-Feng
authors.initials: YF
authors.lastname: Zou
authors.affiliation: Department of Breast Surgery, The Third Hospital of Nanchang, Nanchang, Jiangxi 330006, P.R. China.
authors.forename: Chun-Wei
authors.initials: CW
authors.lastname: Xie
authors.affiliation: Department of Breast Surgery, The Third Hospital of Nanchang, Nanchang, Jiangxi 330006, P.R. China.
authors.forename: Shi-Xin
authors.initials: SX
authors.lastname: Yang
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China.
authors.forename: Jian-Ping
authors.initials: JP
authors.lastname: Xiong
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D001940:Breast / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000001:Calcimycin / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D000072261:Dishevelled Proteins / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects*; D005260:Female; D006801:Humans; D012265:Ribonucleotides / Q000494:pharmacology; D060449:Wnt Signaling Pathway / Q000187:drug effects*
chemical_list: C000606584:DVL3 protein, human; D000072261:Dishevelled Proteins; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D000001:Calcimycin; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide