Journal Article

Transformation of immortalized colorectal crypt cells by microcystin involving constitutive activation of Akt and MAPK cascade

Yongliang Zhu, Xian Zhong, Shu Zheng, Zhen Ge, Qin Du and Suzhang Zhang

in Carcinogenesis

Volume 26, issue 7, pages 1207-1214
Published in print July 2005 | ISSN: 0143-3334
Published online March 2005 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgi069
Transformation of immortalized colorectal crypt cells by microcystin involving constitutive activation of Akt and MAPK cascade

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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.

Keywords: 17-AAG, 17-(allylamino)-17-demethoxy-geldanamycin; CRC, colorectal cancer; DMH, 1,2-dimethylhydrazine; DMSO, dimethyl sulfoxide; FAK, focal adhesion kinase; GSK-3, glycogen synthase kinase-3; IVT, in vitro transcription; MAPK, mitogen-activated protein kinase; MAPKAPK2, MAPK activated protein kinase 2; MCLR, Microcystin LR; MTT, methyl thiazolyl tetrazolium; PI3K, phosphatidylinositol 3 kinase; PP1, serine/threonine protein phosphatase 1; SB203580, 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole; SP600125, 1,9-pyrazoloanthrone; SV40 LT, SV 40 large T antigen

Journal Article.  7004 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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