Document Detail


Inactivation of Rho GTPases by p190 RhoGAP reduces human pancreatic cancer cell invasion and metastasis.
MedLine Citation:
PMID:  16776779     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
A number of small GTPases are involved in cancer cell proliferation, migration and invasion, acting as molecular switches that cycle between GTP- and GDP-bound states. GTPase-activating proteins (GAPs) have been established as a major class of negative regulators of Rho GTPase signaling. To investigate the biological function of p190 RhoGAP toward RhoA in cancer cell invasion and metastasis, we generated a chimera made of the RhoGAP domain of p190 and the C-terminus of RhoA (p190-RhoA chimera), and transfected it into human pancreatic cancer cells, AsPC-1. Epidermal growth factor (EGF)-induced activation of RhoA, as well as RhoB and RhoC, to a lesser extent, was significantly inhibited in p190-RhoA chimera-transfected AsPC-1 cells compared with that of control cells (mock-infected), when assessed by pull-down assay for GTP-bound RhoA, RhoB, and RhoC, respectively. EGF-induced invasion of p190-RhoA chimera transfectants was significantly inhibited compared with that of mock-infected cells in a modified Boyden chamber assay. Furthermore, the mice injected intrasplenically with AsPC-1 cells that overexpressed the p190-RhoA chimera had a marked reduction in the number and size of metastatic nodules in the liver. These data suggest that the inhibitory action of p190 RhoGAP toward RhoA offers a novel approach to the treatment of invasion and metastasis of cancer cells.
Authors:
Toshiyuki Kusama; Mutsuko Mukai; Hiroko Endo; Osamu Ishikawa; Masaharu Tatsuta; Hiroyuki Nakamura; Masahiro Inoue
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2006-06-14
Journal Detail:
Title:  Cancer science     Volume:  97     ISSN:  1347-9032     ISO Abbreviation:  Cancer Sci.     Publication Date:  2006 Sep 
Date Detail:
Created Date:  2006-08-18     Completed Date:  2006-10-18     Revised Date:  2011-09-27    
Medline Journal Info:
Nlm Unique ID:  101168776     Medline TA:  Cancer Sci     Country:  England    
Other Details:
Languages:  eng     Pagination:  848-53     Citation Subset:  IM    
Affiliation:
Department of Biochemistry, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.
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MeSH Terms
Descriptor/Qualifier:
Animals
Blotting, Western
Carrier Proteins / genetics,  metabolism*
Cell Line, Tumor
Chimera
DNA-Binding Proteins
Enzyme Activation / drug effects,  physiology
Epidermal Growth Factor / pharmacology
GTPase-Activating Proteins
Guanine Nucleotide Exchange Factors
Humans
Mice
Mitogen-Activated Protein Kinases / drug effects,  metabolism
Neoplasm Invasiveness / physiopathology*
Neoplasm Transplantation
Neoplasms, Experimental / pathology
Pancreatic Neoplasms / enzymology,  pathology*
Repressor Proteins
Transfection
rho GTP-Binding Proteins / drug effects,  genetics,  metabolism*
Chemical
Reg. No./Substance:
0/ARHGAP35 protein, human; 0/ARHGAP5 protein, human; 0/Arhgap5 protein, mouse; 0/Carrier Proteins; 0/DNA-Binding Proteins; 0/GTPase-Activating Proteins; 0/Grlf1 protein, mouse; 0/Guanine Nucleotide Exchange Factors; 0/Repressor Proteins; 62229-50-9/Epidermal Growth Factor; EC 2.7.11.24/Mitogen-Activated Protein Kinases; EC 3.6.5.2/rho GTP-Binding Proteins

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