Thermostable Direct Hemolysin Downregulates Human Colon Carcinoma Cell Proliferation with the Involvement of E-Cadherin, and β-Catenin/Tcf-4 Signaling

Abstract

BackgroundColon cancers are the frequent causes of cancer mortality worldwide. Recently bacterial toxins have received marked attention as promising approaches in the treatment of colon cancer. Thermostable direct hemolysin (TDH) secreted by Vibrio parahaemolyticus causes influx of extracellular calcium with the subsequent rise in intracellular calcium level in intestinal epithelial cells and it is known that calcium has antiproliferative activity against colon cancer.Key ResultsIn the present study it has been shown that TDH, a well-known traditional virulent factor inhibits proliferation of human colon carcinoma cells through the involvement of CaSR in its mechanism. TDH treatment does not induce DNA fragmentation, nor causes the release of lactate dehydrogenase. Therefore, apoptosis and cytotoxicity are not contributing to the TDH-mediated reduction of proliferation rate, and hence the reduction appears to be caused by decrease in cell proliferation. The elevation of E-cadherin, a cell adhesion molecule and suppression of β-catenin, a proto-oncogene have been observed in presence of CaSR agonists whereas reverse effect has been seen in presence of CaSR antagonist as well as si-RNA in TDH treated cells. TDH also triggers a significant reduction of Cyclin-D and cdk2, two important cell cycle regulatory proteins along with an up regulation of cell cycle inhibitory protein p27Kip1 in presence of CaSR agonists.ConclusionTherefore TDH can downregulate colonic carcinoma cell proliferation and involves CaSR in its mechanism of action. The downregulation occurs mainly through the involvement of E-cadherin-β-catenin mediated pathway and the inhibition of cell cycle regulators as well as upregulation of cell cycle inhibitors.

Biofilm competency of Desulfovibrio vulgaris Hildenborough facilitates colonization in the gut and represses adenoma development in a rat model of colon cancer

“…They secrete a wide range of proteins including adhesins, cyclases, metalloproteasephosphatases, hydrolases, hemolysins etc. ( (Chowdhury et al, 2011). This disparity in the role of the hemolysins is a potential factor affecting the mechanism of reduced burden in the bio lm-competent strain-treated PIRC rats and warrants further investigation in future studies.…”

Biofilm competency of Desulfovibrio vulgaris Hildenborough facilitates colonization in the gut and represses adenoma development in a rat model of colon cancer

“…The copyright holder for this preprint (which this version posted July 26, 2022. ; https://doi.org/10.1101/2022.07.26.501613 doi: bioRxiv preprint Some reports have suggested that hemolysins promote tumorigenesis (Hernández-Luna et al, 2016), while others propose that bacterial hemolysins could be protective against colon cancer (Chowdhury et al, 2011). This disparity in the role of the hemolysins is a potential factor affecting the mechanism of reduced burden in the biofilm-competent strain-treated PIRC rats and warrants further investigation in future studies.…”

“…One of the functions of the RTX family of genes is the production of alpha-hemolysin, reported in several Gram-negative bacteria (including E.coli) to be capable of causing urinary tract infections and host tissue damage (Bauer and Welch, 1996;Sasaki et al, 2009;Vigil et al, 2012). Some reports have suggested that hemolysins promote tumorigenesis (Hernández-Luna et al, 2016), while others propose that bacterial hemolysins could be protective against colon cancer (Chowdhury et al, 2011). This disparity in the role of the hemolysins is a potential factor affecting the mechanism of reduced burden in the biofilm-competent strain-treated PIRC rats and warrants further investigation in future studies.…”

Regulation of Ca2+Signaling in Pulmonary Hypertension

“…A variety of cancers have also been associated by an absence or loss of CaSR; pituitary adenomas and colorectal cancer [99-101]. In colorectal cancer a decreased CaSR expression in the colonic epithelium is evident; it is believed at CaSR acts to promote the down-regulation of beta-catenin-mediated transcriptional activation having subsequent effects on cell proliferation [87,102,103]. Functional expression is also identified in the cardiovascular system [91,104,105] and, most recently, in the pulmonary vasculature where it has been implicated in the pathogenesis of PH [106-109].…”