Document Detail


Transformation of immortalized colorectal crypt cells by microcystin involving constitutive activation of Akt and MAPK cascade.
MedLine Citation:
PMID:  15774489     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Yongliang Zhu; Xian Zhong; Shu Zheng; Zhen Ge; Qin Du; Suzhang Zhang
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2005-03-17
Journal Detail:
Title:  Carcinogenesis     Volume:  26     ISSN:  0143-3334     ISO Abbreviation:  Carcinogenesis     Publication Date:  2005 Jul 
Date Detail:
Created Date:  2005-06-23     Completed Date:  2005-07-29     Revised Date:  2012-06-22    
Medline Journal Info:
Nlm Unique ID:  8008055     Medline TA:  Carcinogenesis     Country:  England    
Other Details:
Languages:  eng     Pagination:  1207-14     Citation Subset:  IM    
Affiliation:
Department of Gastroenterology and Cancer Institute, Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China.
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MeSH Terms
Descriptor/Qualifier:
Cell Culture Techniques
Cell Proliferation
Cell Transformation, Neoplastic*
Colon / cytology
Colorectal Neoplasms / genetics*,  physiopathology*
Humans
JNK Mitogen-Activated Protein Kinases / metabolism
MAP Kinase Kinase 4
Microcystins
Mitogen-Activated Protein Kinase Kinases / metabolism*
Peptides, Cyclic / pharmacology*
Precancerous Conditions
Protein-Serine-Threonine Kinases / physiology*
Proto-Oncogene Proteins / physiology*
Proto-Oncogene Proteins c-akt
Rectum / cytology
p38 Mitogen-Activated Protein Kinases / metabolism
Chemical
Reg. No./Substance:
0/Microcystins; 0/Peptides, Cyclic; 0/Proto-Oncogene Proteins; 77238-39-2/microcystin; EC 2.7.11.1/AKT1 protein, human; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 2.7.11.1/Proto-Oncogene Proteins c-akt; EC 2.7.11.24/JNK Mitogen-Activated Protein Kinases; EC 2.7.11.24/p38 Mitogen-Activated Protein Kinases; EC 2.7.12.2/MAP Kinase Kinase 4; EC 2.7.12.2/Mitogen-Activated Protein Kinase Kinases

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