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Research Article

Nicotine mediated activation of Pak1/NFkB cascade in pancreatic cancer cells – A pilot study

Authors:

Sankar Jagadeeshan ,

Department of Genetics, Dr ALM Post Graduate Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai 600113, India, IN
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M. Manu Prasad,

Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Poojapura, Thycaud P.O., Thiruvananthapuram 695014, India, IN
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Kalesh Sadasivan,

Department of Plastic and Reconstructive Surgery, Government Medical College, Thiruvananthapuram 695011, India, IN
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G. Gejoe,

Department of General Surgery, Government Medical College, Thiruvananthapuram 695011, India, IN
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Hemdev Bhoopalan,

Department of Human Genetics, Sri Ramachandra University, Porur, Chennai 600116, India, IN
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P. Ashraf,

Department of Genetics, Dr ALM Post Graduate Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai 600113, India, IN
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Manjula Sudhakaran,

Prism Foundation, Bangalore 560076, India, IN
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S. Shabin Ghouse,

Prism Foundation, Bangalore 560076, India, IN
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Raghunathan Malathia

Department of Genetics, Dr ALM Post Graduate Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai 600113, India, IN
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Abstract

Background

Tobacco smoking is a major established risk factor for pancreatic cancer (PC), increasing the incidence up to six fold depending on the duration and intensity of smoking. Nicotine is a key toxin in tobacco and cigarette, which may contribute to development of pancreatitis and PC. Our previous studies revealed an aberrant expression of Pak1 in PC as compared to normal pancreas and its association with cancer progression, tumor angiogenesis, drug resistance and metastasis. Here, we explore a potential link between Pak1 expression and smoking-mediated PC pathogenesis and the use of Pak1 inhibitors to curtail this association.

Methods

Mia Pa Ca 2 cell line was obtained from NCCS, Pune and grown in the presence and absence of 0.5 μM (0.112 μg/ml) nicotine hemisulphate salt (5 h) and further nicotine exposed cells were treated with Pak1 inhibitor, IPA-3 (1 h). Protein, mRNA and kinase activity of Pak1 were evaluated. Using human pancreatic cancer tissue, mRNA from smokers (n = 10) and non –smokers (n = 10) were assessed for Pak1 expression.

Results

Nicotine significantly enhanced the expression and kinase activity of Pak1, with subsequent activation of NF-κB signalling cascade in cooperation with other pathways, this effect was blocked by IPA-3. Also, it was observed that pharmacological blockage or silencing of α7-nAChR abrogated nicotine mediated activation of Pak1/NF-κB. Additionally, we demonstrated up-regulated Pak1 mRNA expression in tissue sample from smokers compared to non-smokers.

Conclusion

Our findings suggest probable mechanism of action of nicotine through Pak1 signalling on PC pathogenesis and this could be targeted using Pak1 inhibitors for PC treatment.

How to Cite: Jagadeeshan, S. et al., (2017). Nicotine mediated activation of Pak1/NFkB cascade in pancreatic cancer cells – A pilot study. New Horizons in Translational Medicine. 3(6), pp.284–288. DOI: http://doi.org/10.1016/j.nhtm.2017.06.003
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Published on 15 Jun 2017.
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