Selective depletion of tumour suppressors Deleted in Colorectal Cancer (DCC) and neogenin by environmental and endogenous serine proteases: linking diet, obesity and cancer

Forrest, C. M., McNair, K. , Vincenten, M. C.J., Darlington, L. G. and Stone, T. W. (2016) Selective depletion of tumour suppressors Deleted in Colorectal Cancer (DCC) and neogenin by environmental and endogenous serine proteases: linking diet, obesity and cancer. BMC Cancer, 16, 772. (doi: 10.1186/s12885-016-2795-y) (PMID:27716118) (PMCID:PMC5054602)

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Abstract

Background: The related tumour suppressor proteins Deleted in Colorectal Cancer (DCC) and neogenin are absent or weakly expressed in many cancers, whereas their insertion into cells suppresses oncogenic behaviour. Serine proteases influence the initiation and progression of cancers although the mechanisms are unknown. Methods: The effects of environmental (bacterial subtilisin) and endogenous mammalian (chymotrypsin) serine proteases were examined on protein expression in fresh, normal tissue and human neuroblastoma and mammary adenocarcinoma lines. Cell proliferation and migration assays (chemoattraction and wound closure) were used to examine cell function. Cells lacking DCC were transfected with an ectopic dcc plasmid. Results: Subtilisin and chymotrypsin selectively depleted DCC and neogenin from cells at nanomolar concentrations without affecting related proteins. Cells showed reduced adherence and increased migration, but after washing they re-attached within 24 h, with recovery of protein expression. These effects are induced by chymotryptic activity as they are prevented by chymostatin and the soybean Bowman-Birk inhibitor typical of many plant protease inhibitors. Conclusions: Bacillus subtilis, which secretes subtilisin is widely present in soil, the environment and the intestinal contents, while subtilisin itself is used in meat processing, animal feed probiotics and many household cleaning agents. With chymotrypsin present in chyme, blood and tissues, these proteases may contribute to cancer development by depleting DCC and neogenin. Blocking their activity by Bowman-Birk inhibitors may explain the protective effects of a plant diet. Our findings identify a potential non-genetic contribution to cancer cell behaviour which may explain both the association of processed meats and other factors with cancer incidence and the protection afforded by plant-rich diets, with significant implications for cancer prevention.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Forrest, Dr Caroline and Stone, Professor Trevor and Mcnair, Dr Kara and Vincenten, Miss Maria
Authors: Forrest, C. M., McNair, K., Vincenten, M. C.J., Darlington, L. G., and Stone, T. W.
College/School:College of Medical Veterinary and Life Sciences > Institute of Neuroscience and Psychology
Journal Name:BMC Cancer
Publisher:BioMed Central Ltd.
ISSN:1471-2407
ISSN (Online):1471-2407
Copyright Holders:Copyright © 2016 The Authors
First Published:First published in BMC Cancer 16: 772
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
2188514Pharmacology and rheumatoid research: amino acids, purine and kynurenines in inflammatory disordersTrevor StoneEpsom Medical Research Charity, (EPSOM)UNSPECIFIEDRI NEUROSCIENCE & PSYCHOLOGY