It has been shown by epidemiological and animal studies that
microcystin is an important exogenous factor involved in the
carcinogenesis of
colorectal cancer (CRC). However, details of the mechanism remain unclear. Transformation of colorectal cells is an important initial step in
carcinogenesis. Whether
microcystin is capable of transforming immortalized colorectal crypt cells, and what the mechanism might be, was investigated. In the present study, we demonstrated that immortalized colorectal crypt cells could be transformed by
microcystin. Transformed colorectal crypt cells showed an anchorage-independent growth phenotype, and the proliferation activities of
microcystin-transformed cells were also greater than that of immortalized colorectal crypt cells. The Akt and the p38, JNK of
mitogen-activated protein kinase (MAPK) pathways in
microcystin-transformed cells were found to be constitutively activated. In
microcystin-transformed cells, PI3K,
MAPKAPK2, Akt,
cyclin D1 and
cyclin D3 in the Akt pathway; IQGAP-2, RabGTPase, Rap1GAP, RasGAP, R-Ras, Krev-1 and TC21 of the Ras
GTP/
GDP protein family; and A-Raf, B-Raf and PAK in the Ras/MAPK pathway were all markedly upregulated. However, in positive control cells,
dimethylhydrazine-transformed cells, only the Akt pathway was activated by PI3K, and no evidence of alteration of any molecules of the Ras superfamily was observed. Inhibition of Akt, p38 and JNK activation led to a reduced proliferation of
microcystin-transformed cells. This implies that the constitutive activation of Akt and the p38, JNK of MAPK pathways in
microcystin-transformed cells may be the mechanism by which this important external factor acts in the
carcinogenesis of CRC.