Document Detail


PI3-kinase/Wnt association mediates COX-2/PGE(2) pathway to inhibit apoptosis in early stages of colon carcinogenesis: chemoprevention by diclofenac.
MedLine Citation:
PMID:  20617408     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
In addition to having anti-inflammatory properties, non-steroidal anti-inflammatory drugs (NSAIDs) inhibit neoplastic cell proliferation by inducing apoptosis. Inhibition of cyclooxygenase-2 (COX-2) seemed to be the principal target of NSAIDs, as it is overexpressed in several cancers and catalyzes the synthesis of prostaglandin E₂ (PGE₂), the critical pro-inflammatory molecule. A major role for phosphatidylinositol-3 kinase (PI3-kinase) pathway activation in human tumors has been more recently established. The present study explored the role of PI3-kinase and Wnt molecular pathways in COX-2 and PGE₂ production as well as NSAIDs' chemopreventive effect in colon cancer. 1,2-dimethylhydrazine (DMH) was used for experimental colon cancer model in rat and diclofenac as the preferential COX-2 selective chemopreventive agent. Expression of caspase-3 and caspase-9 was checked in the colonic tissue by immunofluorescence. A decrease was seen in their expressions, indicative of inhibition of apoptosis in the present model. COX-2 mRNA expression as well as PGE₂ levels was elevated after DMH treatment; however, COX-1 mRNA expression was unaltered as seen by reverse transcriptase-polymerase chain reaction (RT-PCR) analysis. DMH also activated PI3-kinase, Akt, Wnt, and β-catenin expressions but reduced the glycogen synthase kinase-3β (GSK-3β) levels. Co-administration of diclofenac with DMH increased the mRNA expression of GSK-3β while inactivating PI3-kinase, Akt, Wnt, and β-catenin. The study suggests that activation of PI3-kinase and Wnt signaling is associated with COX-2/PGE₂ production and in turn inhibition of apoptosis in colon cancer, while diclofenac targeted these pathways to restore apoptosis in the present system.
Authors:
Jasmeet Kaur; Sankar Nath Sanyal
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Publication Detail:
Type:  Journal Article     Date:  2010-07-09
Journal Detail:
Title:  Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine     Volume:  31     ISSN:  1423-0380     ISO Abbreviation:  Tumour Biol.     Publication Date:  2010 Dec 
Date Detail:
Created Date:  2010-10-13     Completed Date:  2010-11-29     Revised Date:  2011-11-02    
Medline Journal Info:
Nlm Unique ID:  8409922     Medline TA:  Tumour Biol     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  623-31     Citation Subset:  IM    
Affiliation:
Department of Biophysics, Panjab University, Chandigarh 160 014, India.
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MeSH Terms
Descriptor/Qualifier:
1,2-Dimethylhydrazine / pharmacology,  therapeutic use
Animals
Anti-Inflammatory Agents, Non-Steroidal / pharmacology,  therapeutic use
Apoptosis / drug effects*,  physiology
Caspase 3 / metabolism
Caspase 9 / metabolism
Colonic Neoplasms / metabolism,  pathology*,  prevention & control
Cyclooxygenase 2 / metabolism*
Cyclooxygenase Inhibitors / pharmacology
Diclofenac / pharmacology*,  therapeutic use
Dinoprostone / metabolism*
Disease Models, Animal
Glycogen Synthase Kinase 3 / metabolism
Male
Phosphatidylinositol 3-Kinases / metabolism*
Proto-Oncogene Proteins c-akt / metabolism
Rats
Rats, Sprague-Dawley
Signal Transduction / drug effects,  physiology
Wnt Proteins / metabolism*
beta Catenin / metabolism
Chemical
Reg. No./Substance:
0/Anti-Inflammatory Agents, Non-Steroidal; 0/Cyclooxygenase Inhibitors; 0/Wnt Proteins; 0/beta Catenin; 15307-86-5/Diclofenac; 363-24-6/Dinoprostone; 540-73-8/1,2-Dimethylhydrazine; EC 1.14.99.1/Cyclooxygenase 2; EC 2.7.1.-/Phosphatidylinositol 3-Kinases; EC 2.7.11.1/Proto-Oncogene Proteins c-akt; EC 2.7.11.1/glycogen synthase kinase 3 beta; EC 2.7.11.26/Glycogen Synthase Kinase 3; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspase 9

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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