Document Detail

Diindolylmethane-mediated Gli1 protein suppression induces anoikis in ovarian cancer cells in vitro and blocks tumor formation ability in vivo.
MedLine Citation:
PMID:  22773833     Owner:  NLM     Status:  MEDLINE    
Anoikis is a cell death that occurs due to detachment of a cell from the extracellular matrix (ECM). Resistance to anoikis is a primary feature of a cell that undergoes metastasis. In this study for the first time, we demonstrated the potential role of Gli1 in anoikis resistance. Treatment of various ovarian cancer cells by different concentrations of diindolylmethane (DIM), an active ingredient of cruciferous vegetables, reduced the anoikis resistance in a concentration-dependent manner. Reduction in anoikis resistance was associated with a decrease in the expression of Gli1 and an increase in the cleavage of poly(ADP-ribose) polymerase (PARP). Sonic hedgehog (Shh) treatment not only increased the expression of Gli1, but also blocked anoikis induced by DIM and abrogated the change in the expression of Gli1 and cleaved PARP by DIM. To confirm the role of Gli1, hedgehog inhibitor cyclopamine, Gli1 siRNA and Gli1(-/-) mouse embryonic fibroblasts (MEFs) were used. Cyclopamine treatment alone significantly reduced anoikis resistance in A2780 and OVCAR-429 cells. Cyclopamine-mediated reduction in anoikis resistance was associated with reduced expression of Gli1 and induction of cleaved PARP. Shh treatment blocked cyclopamine-induced anoikis. Silencing Gli1 expression induced anoikis and cleavage of PARP in A2780 and OVCAR-429 cells. Furthermore, Gli1(-/-) MEFs were more sensitive to anoikis compared with Gli1(+/+) MEFs. Our in vivo studies established that DIM- or cyclopamine-treated ovarian cancer cells under suspension culture conditions drastically lost their ability of tumor formation in vivo in mice. Taken together, our results establish that Gli1 is a critical player in anoikis resistance in ovarian cancer.
Prabodh K Kandala; Sanjay K Srivastava
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2012-07-06
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  287     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2012 Aug 
Date Detail:
Created Date:  2012-08-20     Completed Date:  2012-10-31     Revised Date:  2013-08-20    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  28745-54     Citation Subset:  IM    
Department of Biomedical Sciences, Texas Tech University Health Sciences Center, Amarillo, Texas 79106, USA.
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MeSH Terms
Anoikis / drug effects*,  genetics
Cell Line, Tumor
Drug Resistance, Neoplasm / drug effects*,  genetics
Embryo, Mammalian / metabolism,  pathology
Fibroblasts / metabolism,  pathology
Gene Expression Regulation, Neoplastic / drug effects*,  genetics
Hedgehog Proteins / genetics,  metabolism
Indoles / pharmacology*
Kruppel-Like Transcription Factors / biosynthesis*,  genetics
Mice, Knockout
Ovarian Neoplasms / drug therapy,  genetics,  metabolism*,  pathology
Poly(ADP-ribose) Polymerases / genetics,  metabolism
Veratrum Alkaloids / pharmacology
Grant Support
Reg. No./Substance:
0/Gli protein, mouse; 0/Hedgehog Proteins; 0/Indoles; 0/Kruppel-Like Transcription Factors; 0/Shh protein, mouse; 0/Veratrum Alkaloids; 0/diindolylmethane; EC Polymerases; ZH658AJ192/cyclopamine

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