Cross-talk between G protein-coupled receptor and epidermal growth factor receptor signaling pathways contributes to growth and invasion of head and neck squamous cell carcinoma.
G protein-coupled receptors (GPCR) and the epidermal growth factor receptor (EGFR) are often both overexpressed and contribute to the growth of cancers by activating autocrine pathways. GPCR ligands have been reported to trigger EGFR signaling via receptor cross-talk in cancer cells. Here, we show that GPCR ligands prostaglandin E2 (PGE2) and bradykinin (BK) activate EGFR signaling. Inhibition of EGFR using several strategies, including small-molecule inhibitors and an EGFR-specific antibody, resulted in partial attenuation of signaling downstream of EGFR. PGE2 and BK triggered EGFR signaling by increasing selective autocrine release of transforming growth factor-alpha (TGF-alpha). Inhibition of tumor necrosis factor-alpha-converting enzyme abrogated BK- or PGE2-mediated activation of EGFR signaling. Both PGE2 and BK stimulated head and neck squamous cell carcinoma (HNSCC) invasion via EGFR. Treatment of HNSCC cells with the BK antagonist CU201 resulted in growth inhibition. The combination of CU201 with the EGFR small-molecule inhibitor erlotinib resulted in additive inhibitory effects on HNSCC cell growth in vitro. Inhibition of the PGE2 synthesis pathway with sulindac induced HNSCC cytotoxicity at high doses (EC(50), 620 micromol/L). However, combined inhibition of both EGFR with the tyrosine kinase inhibitor erlotinib and GPCR with sulindac at low doses of 6 and 310 micromol/L, respectively, resulted in synergistic killing of HNSCC tumor cells. Combined blockade of both EGFR and GPCRs may be a rational strategy to treat cancers, including HNSCC that shows cross-talk between GPCR and EGFR signaling pathways.
Thomas
Sufi Mary
SM
Department of Otolaryngology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.
Bhola
Neil E
NE
Zhang
Qing
Q
Contrucci
Sarah C
SC
Wentzel
Abbey L
AL
Freilino
Maria L
ML
Gooding
William E
WE
Siegfried
Jill M
JM
Chan
Daniel C
DC
Grandis
Jennifer Rubin
JR
D000818:Animals; D001920:Bradykinin / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000473:pathology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015232:Dinoprostone / Q000494:pharmacology; D066246:ErbB Receptors / Q000172:deficiency / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D006258:Head and Neck Neoplasms / Q000473:pathology*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009361:Neoplasm Invasiveness; D020239:Receptor Cross-Talk; D043562:Receptors, G-Protein-Coupled / Q000502:physiology*; D015398:Signal Transduction
D043562:Receptors, G-Protein-Coupled; D066246:ErbB Receptors; D015232:Dinoprostone; D001920:Bradykinin