Newcastle disease virus mediated apoptosis and migration inhibition of human oral cancer cells: A probable role of \u03b2-catenin and matrix metalloproteinase-7

Sudhir Morla,Ajay Kumar,Sachin Kumar

doi:10.1038/s41598-019-47244-y

Sudhir Morla, Ajay Kumar + Show 1 more

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https://doi.org/10.1038/s41598-019-47244-y

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Journal: Scientific Reports	Publication Date: Jul 26, 2019
Citations: 15	License type: open-access

Affiliation: Indian Institute of Technology Guwahati

Abstract

Cancer cell metastasis and its dissemination are most enigmatic and challenging aspects in the development of its therapeutics. Newcastle disease virus (NDV) is a well-studied avian paramyxovirus frequently isolated from birds and rarely from mammals. Since the first report of its oncolytic property, many NDV strains were studied for its effect in various cancer cells. In the present study, NDV strain Bareilly was characterized for its apoptotic potential and migration inhibition in human oral cancer cells. The NDV mediated apoptosis was confirmed by flow cytometry, DNA laddering, and immunoblotting. Moreover, NDV decreased the mitochondrial membrane potential suggesting an intrinsic pathway of apoptosis in oral cancer cells. NDV infection in oral cancer cells results in migration inhibition by a reduction in levels of MMP-7. MMP-7 is one of the key target genes of β-catenin. While overexpression of MMP-7 reversed the inhibitory effect of NDV mediated migration suggested its possible involvement. Wnt/β-catenin is an essential pathway for cell growth, differentiation, and metastasis. The involvement of the Wnt/β-catenin pathway in NDV infection has never been reported. Our results showed that NDV dysregulates Wnt/β-catenin by down-regulation of p-Akt and p-GSK3β leading to degradation of β-catenin. Furthermore, NDV infection leads to a reduction in cytoplasmic and nuclear levels of β-catenin. The study will provide us with a better insight into the molecular mechanism of NDV mediated oncolysis and the key cellular partners involved in the process.

Highlights

Newcastle disease virus (NDV) is a well-studied avian paramyxovirus frequently isolated from birds[1,2]
Alteration in Wnt/β-catenin pathway results in translocation of β-catenin to the nucleus resulting in enhanced cell proliferation and aberrant expression of various genes such as; cyclin D1, c-Myc and Matrix metalloproteinases (MMP)-734,39,40
The cytotoxicity of squamous cell carcinoma cell line (SAS) cells following NDV infection was analyzed at different time intervals

Summary

Introduction

Newcastle disease virus (NDV) is a well-studied avian paramyxovirus frequently isolated from birds[1,2]. Since the first report of their oncolytic property, many NDV strains were studied for their effect in various cancer cells[7,8]. Development of NDV as a vector to express foreign genes have been explored to enhance its oncolytic activity[19]. Recombinant NDVs expressing cytokines like IL-2, GM-CSF, IFNγ, and TNF-α have shown an increased level of oncolytic activity in various cancer models as compared to its wild-type strain[20,21]. The role of MMP-7 in NDV mediated migration inhibition has not been explored. The specific purposes of the present study are, to determine the apoptotic potential of NDV strain Bareilly in oral carcinoma cells and to explore the probable molecular mechanism of its migration inhibition. To the best of our knowledge, this is the first report of modulations of MMP-7 and β-catenin upon NDV infection in the cancer cells

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