title: Irigenin, a novel lead from Western Himalayan chemiome inhibits Fibronectin-Extra Domain A induced metastasis in Lung cancer cells.
abstract: Several lines of evidence indicate that Fibronectin Extra Domain A (EDA) promotes metastatic capacity of tumor cells by engaging cell surface α9β1 integrins. This interaction mediated by the C-C loop of EDA activates pro-oncogenic signaling pathways leading to epithelial to mesenchymal transition (EMT) of tumor cells, thus signifying its importance in control of metastatic progression. In this context the present study was designed to explore the active compounds from selected ethno-medicinal plants of western Himalayan region for targeting EDA of Fibronectin in lung carcinoma cells. Structure based informatics for drug designing and screening was employed to generate a lead compound(s) feed that were conformationally and energetically viable. Out of 120 compounds selected, Irigenin showed best binding-affinity with C-C loop of EDA. Irigenin specifically targeted α9β1 and α4β1 integrin binding sites on EDA comprising LEU46, PHE47, PRO48, GLU58, LEU59 and GLN60 in its C-C loop as evaluated by energy decomposition per residue of Irigenin-EDA complex. In-vitro cell motility assays complemented with EDA knock-in and knockdown assays distinctively demonstrated that Irigenin prevents metastatic capacity of lung cancer cells by selectively blocking EDA. The results presented thus project Irigenin as a lead compound to overcome Fibronectin EDA induced metastatic progression in lung carcinoma cells.
authors.affiliation: Department of Biotechnology, University of Kashmir, Srinagar (J and K), 190006, India.|Hybridoma Laboratory, National Institute of Immunology, New Delhi, 110067, India.
authors.forename: Asif
authors.initials: A
authors.lastname: Amin
authors.affiliation: Department of Biotechnology, University of Kashmir, Srinagar (J and K), 190006, India.|Aaidah Life Sciences Pvt. Ltd., New Delhi, 110025, India.
authors.forename: Naveed Anjum
authors.initials: NA
authors.lastname: Chikan
authors.affiliation: Department of Biotechnology, University of Kashmir, Srinagar (J and K), 190006, India.
authors.forename: Taseem A
authors.initials: TA
authors.lastname: Mokhdomi
authors.affiliation: Department of Biotechnology, University of Kashmir, Srinagar (J and K), 190006, India.|Molecular Reproduction, Development &Genetics Lab, Indian Institute of Science, Bangalore, 560 012, India.
authors.forename: Shoiab
authors.initials: S
authors.lastname: Bukhari
authors.affiliation: Department of Biotechnology, University of Kashmir, Srinagar (J and K), 190006, India.
authors.forename: Aabid M
authors.initials: AM
authors.lastname: Koul
authors.affiliation: Department of Biotechnology, University of Kashmir, Srinagar (J and K), 190006, India.
authors.forename: Basit Amin
authors.initials: BA
authors.lastname: Shah
authors.affiliation: Department of Biology, Islamic Azad University, Kāzerūn, Iran.
authors.forename: Fatemeh Rahimi
authors.initials: FR
authors.lastname: Gharemirshamlu
authors.affiliation: Department of Biotechnology, University of Kashmir, Srinagar (J and K), 190006, India.
authors.forename: Asrar H
authors.initials: AH
authors.lastname: Wafai
authors.affiliation: Hybridoma Laboratory, National Institute of Immunology, New Delhi, 110067, India.
authors.forename: Ayub
authors.initials: A
authors.lastname: Qadri
authors.affiliation: Department of Biotechnology, University of Kashmir, Srinagar (J and K), 190006, India.
authors.forename: Raies A
authors.initials: RA
authors.lastname: Qadri
mesh_terms: D000072283:A549 Cells; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000494:pharmacology*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects* / Q000235:genetics; D005353:Fibronectins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D039001:Integrin alpha Chains / Q000235:genetics / Q000378:metabolism; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism; D007529:Isoflavones / Q000737:chemistry / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D000072417:Protein Domains
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D005353:Fibronectins; D039001:Integrin alpha Chains; D019012:Integrin beta1; D007529:Isoflavones; D009363:Neoplasm Proteins; C084613:integrin alpha9; C509874:irigenin