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PI3-kinase/Wnt association mediates COX-2/PGE2 pathway to inhibit apoptosis in early stages of colon carcinogenesis: chemoprevention by diclofenac

  • Research Article
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Tumor Biology

Abstract

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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Notes

  1. Annealing temperatures were β-actin, 61.7°C; COX-1, 61.3°C; COX-2, 60.6°C; PI3-kinase, 57.2°C; Akt, 61.2°C; GSK-3β, 56.4°C; Wnt-1, 62.3°C; and β-catenin, 56.7°C.

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Acknowledgement

Financial assistance from the Council of Scientific and Industrial Research (CSIR), Government of India (37(1308)/07/EMR-II), is gratefully acknowledged.

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  1. Department of Biophysics, Panjab University, Chandigarh, 160 014, India

    Jasmeet Kaur & Sankar Nath Sanyal

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  1. Jasmeet Kaur
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Correspondence to Sankar Nath Sanyal.

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Kaur, J., Sanyal, S.N. PI3-kinase/Wnt association mediates COX-2/PGE2 pathway to inhibit apoptosis in early stages of colon carcinogenesis: chemoprevention by diclofenac. Tumor Biol. 31, 623–631 (2010). https://doi.org/10.1007/s13277-010-0078-9

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  • DOI: https://doi.org/10.1007/s13277-010-0078-9

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