Toll-like recepwtor 2 induces adenosine receptor A2a and promotes human squamous carcinoma cell growth via extracellular signal regulated kinases 1/2

Chithra Devi Palani, Lalitha Ramanathapuram, Aroonwan Lam-ubol, Zoya B. Kurago

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)6814-6829
Number of pages16
JournalOncotarget
Volume9
Issue number6
DOIs
StatePublished - Jan 1 2018

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Purinergic P1 Receptors
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
Squamous Cell Carcinoma
Growth
Toll-Like Receptors
Purinergic P1 Receptor Agonists
Toll-Like Receptor 2
Caspase 3
Ligands
Cellular Microenvironment
Cell Line
Tumor Microenvironment
MAP Kinase Signaling System
NF-kappa B
Extracellular Signal-Regulated MAP Kinases
Keratinocytes
Up-Regulation
Phosphorylation
Cell Proliferation

Keywords

  • Adenosine receptors (AR)
  • MAPK
  • Oral cancer
  • Squamous cell carcinoma (SCC)
  • Toll-like receptor (TLR)2

ASJC Scopus subject areas

  • Oncology

Cite this

Toll-like recepwtor 2 induces adenosine receptor A2a and promotes human squamous carcinoma cell growth via extracellular signal regulated kinases 1/2. / Palani, Chithra Devi; Ramanathapuram, Lalitha; Lam-ubol, Aroonwan; Kurago, Zoya B.

In: Oncotarget, Vol. 9, No. 6, 01.01.2018, p. 6814-6829.

Research output: Contribution to journalArticle

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