title: Cardamonin, a chalcone, inhibits human triple negative breast cancer cell invasiveness by downregulation of Wnt/β-catenin signaling cascades and reversal of epithelial-mesenchymal transition.
abstract: Cardamonin (CD), an active chalconoid, has shown potent anticancer effects in preclinical studies; however, the effect and underlying mechanism of CD for the treatment of triple negative breast cancer (TNBC) is unclear. This study aims to examine the cytotoxic effects of CD and investigate the underlying mechanism in human TNBC cells. The results show that CD exhibits cytotoxicity by inducing apoptosis and cell cycle arrest in TNBC cells via modulation of Bcl-2, Bax, cyt-C, cleaved caspase-3, and PARP. We find that CD significantly increases expression of the epithelial marker E-cadherin, while reciprocally decreasing expression of mesenchymal markers such as snail, slug, and vimentin in BT-549 cells. In parallel with epithelial-mesenchymal transition (EMT) reversal, CD down regulates invasion and migration of BT-549 cells. CD markedly reduces stability and nuclear translocation of β-catenin, accompanied with downregulation of β-catenin target genes. Using the TopFlash luciferase reporter assay, we reveal CD as a specific inhibitor of the Wnt3a-induced signaling. These results suggest the involvement of the Wnt/β-catenin signaling in the CD-induced EMT reversion of BT-549 cells. Notably, CD restores the glycogen synthase kinase-3β (GSK3β) activity, required for β-catenin destruction via the proteasome-mediated system, by inhibiting the phosphorylation of GSK3β by Akt. These occurrences ultimately lead to the blockage of EMT and the invasion of TNBC cells. Further antitumor activity of CD was tested in 4T1 (TNBC cells) induced tumor and it was found that CD significantly inhibited the tumor volume at dose of 5 mg/kg-treated mice. © 2016 BioFactors, 43(2):152-169, 2017.
authors: Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education & Research (NIPER-Hyderabad), Hyderabad, Telangana, India.
authors: Shweta
authors: S
authors: Shrivastava
authors: Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education & Research (NIPER-Hyderabad), Hyderabad, Telangana, India.
authors: Manish Kumar
authors: MK
authors: Jeengar
authors: Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education & Research (NIPER-Hyderabad), Hyderabad, Telangana, India.
authors: Dinesh
authors: D
authors: Thummuri
authors: Department of Pharmacology and Toxicology, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland.
authors: Alexey
authors: A
authors: Koval
authors: Department of Pharmacology and Toxicology, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland.|School of Biomedicine, Far Eastern Federal University, Vladivostok, Russia.
authors: Vladimir L
authors: VL
authors: Katanaev
authors: Institute for Stem Cell Biology and Regenerative Medicine (inStem), NCBS-TIFR, UAS-GKVK, Bengaluru, Karnataka, India.
authors: Srujan
authors: S
authors: Marepally
authors: Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education & Research (NIPER-Hyderabad), Hyderabad, Telangana, India.
authors: V G M
authors: VGM
authors: Naidu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D047188:Chalcones / Q000008:administration & dosage*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D000071679:Glycogen Synthase Kinase 3 beta / Q000096:biosynthesis; D006801:Humans; D051379:Mice; D009361:Neoplasm Invasiveness / Q000235:genetics; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D060449:Wnt Signaling Pathway / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D047188:Chalcones; D009363:Neoplasm Proteins; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C436747:cardamonin
keywords: cardamonin; epithelial-mesenchymal transition; glycogen synthase kinase-3β; triple negative breast cancer; β-catenin