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

Sankar Jagadeeshan, M. Manu Prasad, Kalesh Sadasivan, G. Gejoe, Hemdev Bhoopalan, P. Ashraf, Manjula Sudhakaran, S. Shabin Ghouse, Raghunathan Malathi

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)284-288
Number of pages5
JournalNew Horizons in Translational Medicine
Volume3
Issue number6
DOIs
StatePublished - 1 Mar 2017
Externally publishedYes

Keywords

  • Inhibitor
  • IPA-3
  • Nicotine
  • Pak1
  • Pancreatic cancer
  • Smoking

ASJC Scopus subject areas

  • Medicine (all)

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