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

Sufi Mary Thomas, Neil E. Bhola, Qing Zhang, Sarah C. Contrucci, Abbey L. Wentzel, Maria L. Freilino, William E. Gooding, Jill M. Siegfried, Daniel C. Chan, Jennifer Rubin Grandis

Research output: Contribution to journalArticle

102 Citations (Scopus)

Abstract

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-α (TGF-α). Inhibition of tumor necrosis factor-α-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 (EC50, 620 μmol/L). However, combined inhibition of both EGFR with the tyrosine kinase inhibitor erlotinib and GPCR with sulindac at low doses of 6 and 310 μmol/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.

Original languageEnglish (US)
Pages (from-to)11831-11839
Number of pages9
JournalCancer Research
Volume66
Issue number24
DOIs
StatePublished - Dec 15 2006
Externally publishedYes

Fingerprint

G-Protein-Coupled Receptors
Epidermal Growth Factor Receptor
Growth
Dinoprostone
Bradykinin
Sulindac
Carcinoma, squamous cell of head and neck
Receptor Cross-Talk
Ligands
Neoplasms
Transforming Growth Factors
Head and Neck Neoplasms
Protein-Tyrosine Kinases
Tumor Necrosis Factor-alpha

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

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. / Thomas, Sufi Mary; Bhola, Neil E.; Zhang, Qing; Contrucci, Sarah C.; Wentzel, Abbey L.; Freilino, Maria L.; Gooding, William E.; Siegfried, Jill M.; Chan, Daniel C.; Grandis, Jennifer Rubin.

In: Cancer Research, Vol. 66, No. 24, 15.12.2006, p. 11831-11839.

Research output: Contribution to journalArticle

Thomas, Sufi Mary ; Bhola, Neil E. ; Zhang, Qing ; Contrucci, Sarah C. ; Wentzel, Abbey L. ; Freilino, Maria L. ; Gooding, William E. ; Siegfried, Jill M. ; Chan, Daniel C. ; Grandis, Jennifer Rubin. / 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. In: Cancer Research. 2006 ; Vol. 66, No. 24. pp. 11831-11839.
@article{e57733da935b4664be7d9c8dbb8d2e41,
title = "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",
abstract = "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-α (TGF-α). Inhibition of tumor necrosis factor-α-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 (EC50, 620 μmol/L). However, combined inhibition of both EGFR with the tyrosine kinase inhibitor erlotinib and GPCR with sulindac at low doses of 6 and 310 μmol/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.",
author = "Thomas, {Sufi Mary} and Bhola, {Neil E.} and Qing Zhang and Contrucci, {Sarah C.} and Wentzel, {Abbey L.} and Freilino, {Maria L.} and Gooding, {William E.} and Siegfried, {Jill M.} and Chan, {Daniel C.} and Grandis, {Jennifer Rubin}",
year = "2006",
month = "12",
day = "15",
doi = "10.1158/0008-5472.CAN-06-2876",
language = "English (US)",
volume = "66",
pages = "11831--11839",
journal = "Cancer Research",
issn = "0008-5472",
number = "24",

}

TY - JOUR

T1 - 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

AU - Thomas, Sufi Mary

AU - Bhola, Neil E.

AU - Zhang, Qing

AU - Contrucci, Sarah C.

AU - Wentzel, Abbey L.

AU - Freilino, Maria L.

AU - Gooding, William E.

AU - Siegfried, Jill M.

AU - Chan, Daniel C.

AU - Grandis, Jennifer Rubin

PY - 2006/12/15

Y1 - 2006/12/15

N2 - 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-α (TGF-α). Inhibition of tumor necrosis factor-α-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 (EC50, 620 μmol/L). However, combined inhibition of both EGFR with the tyrosine kinase inhibitor erlotinib and GPCR with sulindac at low doses of 6 and 310 μmol/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.

AB - 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-α (TGF-α). Inhibition of tumor necrosis factor-α-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 (EC50, 620 μmol/L). However, combined inhibition of both EGFR with the tyrosine kinase inhibitor erlotinib and GPCR with sulindac at low doses of 6 and 310 μmol/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.

UR - http://www.scopus.com/inward/record.url?scp=33846260178&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33846260178&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-06-2876

DO - 10.1158/0008-5472.CAN-06-2876

M3 - Article

C2 - 17178880

AN - SCOPUS:33846260178

VL - 66

SP - 11831

EP - 11839

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 24

ER -