title: Cytomodulin-1, a synthetic peptide abrogates oncogenic signaling pathways to impede invasion and angiogenesis in the hamster cheek pouch carcinogenesis model.
abstract: Constitutive activation of the various oncogenic signaling pathways plays a pivotal role in promoting malignant transformation. The aim of this study was to investigate the therapeutic potential of a synthetic bioactive heptapeptide cytomodulin-1 (CM-1) against hamster cheek pouch carcinomas based on its influence on the predominant carcinogenic signaling pathways - NF-κB, TGFβ, and Wnt/β-catenin and their downstream target events invasion and angiogenesis. Topical application of CM-1 to DMBA-painted hamsters significantly inhibited activation of the canonical NF-κB pathway by blocking kinase activity of IKKβ and increasing the cytosolic accumulation of the inhibitor IκB-α. In addition, CM-1 inactivated IKKβ by disrupting IKKβ/Nemo interactions. CM-1 also hampered the activation of TGFβ and Wnt/β-catenin signaling by averting the phosphorylation of the key upstream ser/thr kinases TGFβ RI and GSK-3β respectively. Attenuation of these oncogenic signaling pathways by CM-1 also mitigated invasion and angiogenesis by suppressing the expression of pro-invasive matrix metalloproteinases, pro-angiogenic VEGF and HIF-1α and upregulating the anti-angiogenic TIMP-2. Synthetic peptides such as CM-1 that target multiple key molecules in oncogenic signaling pathways and their downstream events are ideal candidate agents for cancer chemotherapy.
authors.affiliation: Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar 608 002, Tamil Nadu, India.
authors.forename: K
authors.initials: K
authors.lastname: Kavitha
authors.affiliation: Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar 608 002, Tamil Nadu, India.
authors.forename: T
authors.initials: T
authors.lastname: Kranthi Kiran Kishore
authors.affiliation: Bioengineering, University of California, San Francisco and Berkeley, USA.
authors.forename: R S
authors.initials: RS
authors.lastname: Bhatnagar
authors.affiliation: Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar 608 002, Tamil Nadu, India. Electronic address: s_nagini@yahoo.com.
authors.forename: S
authors.initials: S
authors.lastname: Nagini
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000187:drug effects*; D002610:Cheek / Q000473:pathology; D006224:Cricetinae; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000096:biosynthesis; D000071679:Glycogen Synthase Kinase 3 beta; D016328:NF-kappa B / Q000096:biosynthesis; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D010455:Peptides / Q000008:administration & dosage* / Q000138:chemical synthesis; D015398:Signal Transduction / Q000187:drug effects*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
chemical_list: D016328:NF-kappa B; D010455:Peptides; D042461:Vascular Endothelial Growth Factor A; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3
keywords: Angiogenesis; Cytomodulin-1; NBD; NF-κB; TGFβ; Wnt/β-catenin