Research Papers:
Tolfenamic acid-induced alterations in genes and pathways in pancreatic cancer cells
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Abstract
Umesh T. Sankpal1, Steve Goodison2, Michelle Jones-Pauley1, Myrna Hurtado3, Fan Zhang3, Riyaz Basha1,3
1Texas College of Osteopathic Medicine, University of North Texas Health Science Center, TX, USA
2Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL, USA
3Institute for Molecular Medicine, University of North Texas Health Science Center, TX, USA
Correspondence to:
Riyaz Basha, email: [email protected]
Keywords: tolfenamic acid, pancreatic cancer, Sp1, microarray analysis
Received: November 04, 2016 Accepted: January 05, 2017 Published: January 14, 2017
ABSTRACT
Non-steroidal anti-inflammatory drugs (NSAIDs) are being tested extensively for their role in the treatment and prevention of several cancers. Typically NSAIDs exhibit anti-tumor activities via modulation of cyclooxygenase (COX)-dependent mechanisms, however, an anti-cancer NSAID tolfenamic acid (TA) is believed to work through COX-independent pathways. Results from our laboratory and others have demonstrated the anti-cancer activity of TA in various cancer models including pancreatic cancer. TA has been shown to modulate certain cellular processes including, apoptosis, reactive oxygen species and signaling. In this study, molecular profiling was performed to precisely understand the mode of action of TA. Three pancreatic cancer cell lines, L3.6pl, MIA PaCa-2, and Panc1 were treated with TA (50 μM for 48 h) and the changes in gene expression was evaluated using the Affymetrix GeneChip Human Gene ST Array platform. Microarray results were further validated using quantitative PCR for seven genes altered by TA treatment in all three cell lines. Functional analysis of differentially expressed genes (2 fold increase or decrease, p < 0.05) using Ingenuity Pathway Analysis software, revealed that TA treatment predominantly affected the genes involved in cell cycle, cell growth and proliferation, and cell death and survival. Promoter analysis of the differentially expressed genes revealed that they are enriched for Sp1 binding sites, suggesting that Sp1 could be a major contributor in mediating the effect of TA. The gene expression studies identified new targets involved in TA’s mode of action, while supporting the hypothesis about the association of Sp1 in TA mediated effects in pancreatic cancer.
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