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

Caroline M Forrest,Maria C J Vincenten,Trevor W Stone,L Gail Darlington,Kara Mcnair

doi:10.1186/s12885-016-2795-y

Caroline M Forrest, Maria C J Vincenten + Show 3 more

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https://doi.org/10.1186/s12885-016-2795-y

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Journal: BMC cancer	Publication Date: Oct 6, 2016
Citations: 14	License type: cc-by

Affiliation: University of Glasgow, Ashtead Hospital

Abstract

BackgroundThe 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.MethodsThe 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.ResultsSubtilisin 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2795-y) contains supplementary material, which is available to authorized users.

Highlights

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
Expression of the tumour suppressor proteins Deleted in Colorectal Cancer (DCC) or the structurally related protein neogenin is reduced in many cancers, the extent of loss compared with control tissue correlating with degree of metastasis and with poor patient prognosis [1,2,3,4,5,6,7,8]
These proteins include unco-ordinated5C (Unc-5C), another dependence receptor for netrin which can complex with DCC and which is absent from a variety of cancers [64,65,66,67]; Unco-ordinated locomotion (Unc)-5A: to assess the selectivity of serine proteases for unc5 family members; the small GTPase enzyme Ras homologue A (RhoA) [68, 69]; Sonic hedgehog (Shh), a secreted protein involved in embryonic morphogenesis, cell location and polarisation [70, 71] and which modulates the expression of neogenin and netrin [72]

Summary

Introduction

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. Reduced neogenin expression has a prominent association with cancers in the CNS and mammary tissues [21, 24,25,26] Both DCC and neogenin are involved in defining the balance between cell survival or death and between differentiation and de-differentiation towards an un-regulated, hyper-proliferative and potentially oncogenic phenotype [27,28,29]. They are receptors for the ligand netrin, an extracellular, secreted protein. If DCC or neogenin are absent, this mechanism cannot operate and proliferation or migration will proceed unchecked [34]

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