title: Thermostable direct hemolysin downregulates human colon carcinoma cell proliferation with the involvement of E-cadherin, and β-catenin/Tcf-4 signaling.
abstract: BACKGROUND
  Colon 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.
  
  
  RESULTS
  In 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 p27(Kip1) in presence of CaSR agonists.
  
  
  CONCLUSIONS
  Therefore 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.
authors.affiliation: Division of Pathophysiology, National Institute of Cholera and Enteric Diseases, Beliaghata, Kolkata, India.
authors.forename: Pinki
authors.initials: P
authors.lastname: Chowdhury
authors.forename: Debasis
authors.initials: D
authors.lastname: Pore
authors.forename: Nibedita
authors.initials: N
authors.lastname: Mahata
authors.forename: Poulomee
authors.initials: P
authors.lastname: Karmakar
authors.forename: Amit
authors.initials: A
authors.lastname: Pal
authors.forename: Manoj K
authors.initials: MK
authors.lastname: Chakrabarti
mesh_terms: D001483:Base Sequence; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism*; D015820:Cadherins / Q000378:metabolism*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000473:pathology*; D017931:DNA Primers; D015536:Down-Regulation; D006460:Hemolysin Proteins / Q000378:metabolism*; D006801:Humans; D000090063:Proto-Oncogene Mas; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D015820:Cadherins; D017931:DNA Primers; D006460:Hemolysin Proteins; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors; D051176:beta Catenin