Toll-like receptor 2 induces adenosine receptor A2a and promotes human squamous carcinoma cell growth via extracellular signal regulated kinases ½
Metrics: PDF 809 views | HTML 1168 views | ?
Chithra Devi Palani1, Lalitha Ramanathapuram2, Aroonwan Lam-ubol3 and Zoya B. Kurago1,4
1Dental College of Georgia, Augusta University, Augusta, GA, USA
2Memorial Sloan Kettering Cancer Center, New York, NY, USA
3Faculty of Dentistry Srinakharinwirot University, Wattana, Bangkok, Thailand
4Medical College of Georgia, Augusta University, Augusta, GA, USA
Zoya B. Kurago, email: firstname.lastname@example.org
Keywords: oral cancer; squamous cell carcinoma (SCC); toll-like receptor (TLR)2; adenosine receptors (AR); MAPK
Received: May 11, 2017 Accepted: December 27, 2017 Published: December 30, 2017
Patient treatment for oral squamous cell carcinoma (OSCC) not associated with Human papillomavirus remains problematic. OSCC microenvironment is typically inflamed and colonized by microorganisms, providing ligands for toll-like receptors (TLR). In immune cells TLR2 and TLR4 activate NF-kB and extracellular signal regulated kinase (ERK)1/2 pathways, leading to upregulation of inhibitory adenosine receptors A2a and A2b, and reduction in stimulatory A1 and A3. How TLR and adenosine receptors function in SCC cells is not understood. To address this gap, we evaluated TLR and adenosine receptor expression and function in human OSCC cells and keratinocytes. TLR2 and A2a were co-expressed in pre-cancer and SCC cells of 17 oral specimens. In vitro, 5/6 OSCC lines expressed more TLR2 than TLR1, 4 or 6 mRNA. TLR2 ligands stimulated A2a expression in TLR2-high cell lines, but no A1 or A3 was detected with or without stimuli. In TLR2-high OSCC, TLR2/1, 2/6 and adenosine receptor agonists activated ERK1/2. TLR2-mediated ERK1/2 phosphorylation resulted in accumulation of c-FOS, ERK-dependent cell proliferation and reduced caspase-3 activity. Similar ERK1/2-dependent proliferation and decreased caspase-3 activity were caused by combined TLR2 and adenosine receptor stimuli. We conclude that TLR2 and adenosine receptor agonists, known to be present in the tumor microenvironment, may contribute to OSCC progression in part via direct effects on the ERK1/2 pathway in squamous carcinoma cells.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.