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Association of PI3-kinase and Wnt Signaling in Non-steroidal Anti-Inflammatory Drug-induced Apoptosis in Experimental Colon Cancer

Department of Biophysics, Panjab University, Chandigarh – 160 014, India

*Corresponding author

Dr S N Sanyal

Professor

Department of Biophysics

Panjab University

Chandigarh – 160 014, India

Phone: +911722534122

Email: sanyalpu@gmail.com

Abdel-Nasser Kawde

Tel: +966-3-860-2145

 Fax: +966-3-860-4277

Email: akawde@kfupm.edu.sa

Abstract

In addition to having anti-inflammatory properties, non-steroidal anti-inflammatory drugs (NSAIDs) inhibit neoplastic cell proliferation by inducing apoptosis. Inhibition of cycloxygenase-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 proinflammatory molecule. A major role for phosphatidyl inositol 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 NSAIDs’ chemopreventive effect in colon cancer. 1, 2-dimethylhydrazine was used for experimental colon cancer model and diclofenac as the chemopreventive agent. Protein expression of caspase-3 and 9 and fragmentation of DNA were checked in the colonic tissue. There was a decrease in all the three parameters, indicative of inhibition of apoptosis in the present experimental cancer model. Protein expression of PCNA and proliferation index as determined by both PCNA and BrdU immunostaining were also seen to be increased in the DMH treated animals. DMH upregulated the expression of PI3-kinase, Akt, Wnt and β-catenin, but reduced the GSK-3β levels. Co-administration with diclofenac, while decreasing PI3-kinase, Akt, Wnt and β-catenin, also increased the protein level of GSK-3β thus confirming that NSAIDs target PI3-kinase and Wnt signaling to exert the two important actions – induction of apoptosis and inhibition of cellular proliferation.

Keywords:  NSAID; apoptosis; PI3-kinase; GSK-3β; Wnt.

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