| PI3-kinase/Wnt association mediates COX-2/PGE(2) pathway to inhibit apoptosis in early stages of colon carcinogenesis: chemoprevention by diclofenac. | |
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MedLine Citation:
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PMID: 20617408 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Jasmeet Kaur; Sankar Nath Sanyal |
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Publication Detail:
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Type: Journal Article Date: 2010-07-09 |
Journal Detail:
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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:
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Created Date: 2010-10-13 Completed Date: 2010-11-29 Revised Date: 2011-11-02 |
Medline Journal Info:
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Nlm Unique ID: 8409922 Medline TA: Tumour Biol Country: Netherlands |
Other Details:
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Languages: eng Pagination: 623-31 Citation Subset: IM |
Affiliation:
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Department of Biophysics, Panjab University, Chandigarh 160 014, India. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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1,2-Dimethylhydrazine
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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:
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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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