Saha Subhrajit, Chowdhury Pinki, Pal Amit, Chakrabarti Manoj K
Division of Pathophysiology, National Institute of Cholera and Enteric Diseases, P-33, CIT Road, Scheme-XM, Beliaghata, Calcutta 700010, India.
J Appl Toxicol. 2008 May;28(4):475-83. doi: 10.1002/jat.1297.
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.
早期报道称，分泌性腹泻的主要病原体大肠杆菌热稳定肠毒素（STa），也可通过环磷酸鸟苷（cGMP）介导的钙内流抑制结肠癌细胞的增殖。本研究表明，大肠杆菌STa通过蛋白激酶G（PKG）-细胞外信号调节激酶44/42（ERK44/42）介导的信号通路抑制结肠癌细胞系COLO-205的细胞增殖。这种肠毒素通过下调ERK44/42（丝裂原活化蛋白激酶，MAPK）的活性以及随后转录调节蛋白cMyc的活性来负向调节细胞增殖。STa的抗增殖作用可被鸟苷酸环化酶（GC）抑制剂LY83583和PKG抑制剂KT5823逆转。这表明cGMP依赖性蛋白激酶（PKG）参与了ERK44/42的下调以及随后cMyc活性的失活。此外，研究表明，一种特异性的ERK44/42抑制剂PD98059也可抑制cMyc的激活和细胞增殖，这进一步证实了ERK44/42参与了cMyc的激活。研究还表明，大肠杆菌STa可显著抑制COLO-205细胞中血管内皮生长因子（VEGF，一种强效血管生成因子）的表达，并下调COLO-205细胞表面血管细胞黏附分子-1（VCAM-1，一种强效转移因子）的表达。因此，首次报道大肠杆菌STa通过PKG-ERK44/42介导的途径抑制结肠癌细胞系COLO-205的增殖，其可能在对抗结肠癌的发展中发挥作用。
