Microbial carcinogenic toxins and dietary anti-cancer protectants

Abstract

Several toxins are known which account for the ability of some bacteria to initiate or promote carcinogenesis. These ideas are summarised and evidence is discussed for more specific mechanisms involving chymotrypsin and the bacterial chymotryptic enzyme subtilisin. Subtilisin and Bacillus subtilis are present in the gut and environment and both are used commercially in agriculture, livestock rearing and meat processing. The enzymes deplete cells of tumour suppressors such as deleted in colorectal cancer (DCC) and neogenin, so their potential presence in the food chain might represent an important link between diet and cancer. Over-eating increases secretion of chymotrypsin which is absorbed from the gut and could contribute to several forms of cancer linked to obesity. Inhibition of these serine proteases by Bowman–Birk inhibitors in fruit and vegetables could account for some of the protective effects of a plant-rich diet. These interactions represent previously unknown non-genetic mechanisms for the modification of tumour suppressor proteins and provide a plausible explanation contributing to both the pro-oncogenic effects of meat products and the protective activity of a plant-rich diet. The data suggest that changes to farming husbandry and food processing methods to remove these sources of extrinsic proteases might significantly reduce the incidence of several cancers.

Serine protease modulation of Dependence Receptors and EMT protein expression

“…Since chymotrypsin levels in the intestine and circulation are increased with obesity, and since subtilisin is present in processed meat products and agricultural probiotics, it was suggested that these effects might contribute to the associations between a meat-based diet, obesity and carcinogenesis. [11][12][13] The effects of chymotrypsin and subtilisin were prevented by Bowman-Birk inhibitors found in many fruit and vegetables, consistent with the hypothesis that a plant-rich diet would be protective against cancer 11,12 as concluded by several recent epidemiological studies. 14,15 The present work probes further into the interactions between DCC and serine proteases by assessing their effects on markers of Epithelial-Mesenchymal Transition (EMT).…”

“…6 We have recently reported that the cellular expression of DCC, as well as the structurally and functionally related molecule neogenin- [7][8][9] both of which are receptors for the secreted family of netrin proteins 10 can be depleted by the mammalian serine protease chymotrypsin, which is present in the gastro-intestinal tract and systemic circulation, and by the bacterial chymotryptic enzyme subtilisin. 11,12 The removal of DCC and neogenin was accompanied by increased motility and migration in several transformed cell lines including human neuroblastoma (SH-SY5Y) cells and the mammary adenocarcinoma lines MCF-7 and MDA-MB-231. Since chymotrypsin levels in the intestine and circulation are increased with obesity, and since subtilisin is present in processed meat products and agricultural probiotics, it was suggested that these effects might contribute to the associations between a meat-based diet, obesity and carcinogenesis.…”

Dependence and Guidance Receptors—DCC and Neogenin—In Partial EMT and the Actions of Serine Proteases

“…Contradictory results have also been described when cells were exposed to serine proteases such as mammalian chymotrypsin or the bacterial chymotryptic enzyme subtilisin (27,30). These proteases reduced expression of DCC and neogenin, with changes in the EMT proteins that were not consistent with normal views on their relationship to EMT.…”

“…We have shown that DGR function may be regulated by chymotryptic serine proteases which deplete cells of their DGRs, causing increased cell migration (27), actions that may contribute to dietary effects on cancer incidence (28, 29). Subsequently, the effects of this DGR loss on the induction and progression of EMT were considered to identify any relationship between them, as discussed in the following sections in which the major EMT proteins E-cadherin, N-cadherin, β-catenin and vimentin were investigated (Figure 1) (30).…”

“…Transforming Growth Factor-β, a major regulator of EMT, may regulate vimentin expression and the decrease in E-cadherin (70, 71). However, vimentin is not always increased in migratory cells (72) and simple changes in incubation conditions, such as reducing the proportion of serum, can induce vimentin expression (27,30). Vimentin expression might therefore be linked to the differentiation state of cells rather than their migratory status or capacity (73).…”