Downregulation of human colon carcinoma cell (COLO-205) proliferation through PKG-MAP kinase mediated signaling cascade by E. coli heat stable enterotoxin (STa), a potent anti-angiogenic and anti-metastatic molecule.
It was reported earlier that Escherichia coli heat stable enterotoxin (STa), a major causative agent of secretory diarrhea, can also inhibit the proliferation of colon carcinoma cells with the involvement of cGMP mediated calcium influx. In the present study it is shown that E. coli STa inhibits cell proliferation in the colonic carcinoma cell line COLO-205 by the PKG-ERK44/42 mediated signaling pathway. This enterotoxin negatively regulates cell proliferation by downregulating the activity of ERK44/42(MAPK) and subsequently the activity of a transcription regulatory protein cMyc. The antiproliferative effect of STa was reversed by LY83583, a guanylate cyclase (GC) inhibitor and KT5823, a PKG inhibitor. Thus suggesting the involvement of cGMP dependent protein kinase (PKG) in the downregulation of ERK44/42 and subsequent inactivation of cMyc activity. Moreover, it has been shown that a specific ERK44/42 inhibitor, PD98059, also inhibits cMyc activation and cell proliferation, which further confirms the involvement of ERK44/42 in the activation of cMyc. It is also shown that E. coli STa significantly inhibits the vascular endothelial growth factor (VEGF, a potent angiogenic factor) expression in COLO-205 cells and also downregulates vascular cell adhesion molecule-1 (VCAM-1, a potent metastatic factor) expression on the COLO-205 cell surface. So it is reported for the first time that E. coli STa inhibits the proliferation of the colonic carcinoma cell line COLO-205 by the PKG-ERK44/42 mediated pathway and it may have a role against the development of colon carcinoma.
Saha
Subhrajit
S
Division of Pathophysiology, National Institute of Cholera and Enteric Diseases, P-33, CIT Road, Scheme-XM, Beliaghata, Calcutta 700010, India.
Chowdhury
Pinki
P
Pal
Amit
A
Chakrabarti
Manoj K
MK
D000634:Aminoquinolines / Q000494:pharmacology; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D001427:Bacterial Toxins / Q000494:pharmacology*; D015153:Blotting, Western; D002227:Carbazoles / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000201:enzymology / Q000473:pathology*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004768:Enterotoxins / Q000494:pharmacology*; D029968:Escherichia coli Proteins; D005419:Flavonoids / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D009362:Neoplasm Metastasis; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D013997:Time Factors; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism