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Cucurbitacin B inhibits the stemness and metastatic abilities of NSCLC via downregulation of canonical Wnt/β-catenin signaling axis

Shukla, S
; 
Sinha, S
; 
Khan, S
; 
Kumar, S
; 
Singh, K
; 
Mitra, K
; 
Maurya, R
; 
Meeran, SM
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Genre
Journal Article
Date
2016-02-24
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Department
Subject
A549 Cells
 Animals
 Blotting, Western
 Carcinoma, Non-Small-Cell Lung
 Cell Line, Tumor
 Cell Movement
 Cell Proliferation
 Cell Transformation, Neoplastic
 Down-Regulation
 Epithelial-Mesenchymal Transition
 Female
 Human Umbilical Vein Endothelial Cells
 Humans
 Immunoprecipitation
 Lung Neoplasms
 Mice
 Microscopy, Fluorescence
 Neovascularization, Physiologic
 Nitrosamines
 RNA Interference
 RNA, Small Interfering
 Transforming Growth Factor beta1
 Triterpenes
 Wnt Signaling Pathway
 Wnt3 Protein
 Wnt3A Protein
 beta Catenin
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http://hdl.handle.net/20.500.12613/5146
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DOI
10.1038/srep21860
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.
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Scientific Reports
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