title: Cucurbitacin B inhibits the stemness and metastatic abilities of NSCLC via downregulation of canonical Wnt/β-catenin signaling axis.
abstract: Lack of effective anti-metastatic drugs creates a major hurdle for metastatic lung cancer therapy. For successful lung cancer treatment, there is a strong need of newer therapeutics with metastasis-inhibitory potential. In the present study, we determined the anti-metastatic and anti-angiogenic potential of a natural plant triterpenoid, Cucurbitacin B (CuB) against non-small cell lung cancer (NSCLC) both in vitro and in vivo. CuB demonstrated a strong anti-migratory and anti-invasive ability against metastatic NSCLC at nanomolar concentrations. CuB also showed significant tumor angiogenesis-inhibitory effects as evidenced by the inhibition of migratory, invasive and tube-forming capacities of human umbilical vein endothelial cells. CuB-mediated inhibition of angiogenesis was validated by the inhibition of pre-existing vasculature in chick embryo chorio-allantoic membrane and matrigel plugs. Similarly, CuB inhibited the migratory behavior of TGF-β1-induced experimental EMT model. The CuB-mediated inhibition of metastasis and angiogenesis was attributable to the downregulation of Wnt/β-catenin signaling axis, validated by siRNA-knockdown of Wnt3 and Wnt3a. The CuB-mediated downregulation of Wnt/β-catenin signaling was also validated using 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumorigenesis model in vivo. Collectively, our findings suggest that CuB inhibited the metastatic abilities of NSCLC through the inhibition of Wnt/β-catenin signaling axis.
authors.affiliation: Laboratory of Cancer Epigenetics, Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, India.
authors.forename: Samriddhi
authors.initials: S
authors.lastname: Shukla
authors.affiliation: Laboratory of Cancer Epigenetics, Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, India.
authors.forename: Sonam
authors.initials: S
authors.lastname: Sinha
authors.affiliation: Laboratory of Cancer Epigenetics, Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, India.
authors.forename: Sajid
authors.initials: S
authors.lastname: Khan
authors.affiliation: Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow, India.
authors.forename: Sudhir
authors.initials: S
authors.lastname: Kumar
authors.affiliation: Electron Microscopy Unit, SAIF, CSIR-Central Drug Research Institute, Lucknow, India.
authors.forename: Kavita
authors.initials: K
authors.lastname: Singh
authors.affiliation: Electron Microscopy Unit, SAIF, CSIR-Central Drug Research Institute, Lucknow, India.
authors.forename: Kalyan
authors.initials: K
authors.lastname: Mitra
authors.affiliation: Division of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow, India.
authors.forename: Rakesh
authors.initials: R
authors.lastname: Maurya
authors.affiliation: Laboratory of Cancer Epigenetics, Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, India.|Academy of Scientific and Innovative Research (AcSIR), New Delhi, India.
authors.forename: Syed Musthapa
authors.initials: SM
authors.lastname: Meeran
mesh_terms: D000072283:A549 Cells; D000818:Animals; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D047468:Immunoprecipitation; D008175:Lung Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008856:Microscopy, Fluorescence; D018919:Neovascularization, Physiologic / Q000187:drug effects; D009602:Nitrosamines / Q000633:toxicity; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D014315:Triterpenes / Q000633:toxicity*; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D060508:Wnt3 Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D060509:Wnt3A Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D009602:Nitrosamines; D034741:RNA, Small Interfering; D053773:Transforming Growth Factor beta1; D014315:Triterpenes; D060508:Wnt3 Protein; D060509:Wnt3A Protein; D051176:beta Catenin; C041246:cucurbitacin B; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone