Gastrin-releasing peptide receptor mediates activation of the epidermal growth factor receptor in lung cancer cells

Sufi Mary Thomas; Jennifer Rubin Grandis; Abbey L. Wentzel; William E. Gooding; Vivian Wai Yan Lui; Jill M. Siegfried

doi:10.1593/neo.04454

Gastrin-releasing peptide receptor mediates activation of the epidermal growth factor receptor in lung cancer cells

Sufi Mary Thomas, Jennifer Rubin Grandis, Abbey L. Wentzel, William E. Gooding, Vivian Wai Yan Lui, Jill M. Siegfried

Research output: Contribution to journal › Article › peer-review

58 Scopus citations

Abstract

Gastrin-releasing peptide receptor (GRPR) and the epidermal growth factor receptor (EGFR) are expressed in several cancers including non-small cell lung cancer (NSCLC). Here we demonstrate the activation of EGFR by the GRPR ligand, gastrin-releasing peptide (GRP), in NSCLC cells. GRP induced rapid activation of p44/42 MAPK in lung cancer cells through EGFR. GRP-mediated activation of MAPK in NSCLC cells was abrogated by pretreatment with the anti-EGFR-neutralizing antibody, C225. Pretreatment of NSCLC cells with neutralizing antibodies to the EGFR ligands, TGF-α or HB-EGF, also decreased GRP-mediated MAPK activation. On matrix metalloproteinase (MMP) inhibition, GRP failed to activate MAPK in NSCLC cells. EGF and GRP both stimulated NSCLC proliferation, and inhibition of either EGFR or GRPR resulted in cell death. Combining a GRPR antagonist with the EGFR tyrosine kinase inhibitor, gefitinib, resulted in additive cytotoxic effects. Additive effects were seen at gefitinib concentrations from 1 to 18 μM, encompassing the ID₅₀ values of both gefitinib-sensitive and gefitinib-resistant NSCLC cell lines. Because a major effect of GRPR appears to be promoting the release of EGFR ligand, this study suggests that a greater inhibition of cell proliferation may occur by abrogating EGFR ligand release in consort with inhibition of EGFR.

Original language	English (US)
Pages (from-to)	426-431
Number of pages	6
Journal	Neoplasia
Volume	7
Issue number	4
DOIs	https://doi.org/10.1593/neo.04454
State	Published - Apr 2005
Externally published	Yes

Bibliographical note

Funding Information:
Address all correspondence to: Jill M. Siegfried, PhD, Department of Pharmacology, University of Pittsburgh, E1340, 200 Lothrop Street, Pittsburgh, PA 15213. E-mail: [email protected] 1This work was supported by a grant (U01 CA84968) from the Early Detection Research Network (J.R.G. and J.M.S.), a grant (P50 CA90440) from the Specialized Program of Research Excellence (J.M.S.), and a National Institutes of Health grant (1 R01 CA 098372-01). S.M.T. and V.Y.W.L. were supported by Career Development Awards from the University of Pittsburgh Lung Cancer SPORE. Received 30 June 2004; Revised 1 November 2004; Accepted 3 November 2004.

Keywords

EGFR
GRPR
MAPK
Non-small cell lung cancer
Signal transduction

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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title = "Gastrin-releasing peptide receptor mediates activation of the epidermal growth factor receptor in lung cancer cells",

abstract = "Gastrin-releasing peptide receptor (GRPR) and the epidermal growth factor receptor (EGFR) are expressed in several cancers including non-small cell lung cancer (NSCLC). Here we demonstrate the activation of EGFR by the GRPR ligand, gastrin-releasing peptide (GRP), in NSCLC cells. GRP induced rapid activation of p44/42 MAPK in lung cancer cells through EGFR. GRP-mediated activation of MAPK in NSCLC cells was abrogated by pretreatment with the anti-EGFR-neutralizing antibody, C225. Pretreatment of NSCLC cells with neutralizing antibodies to the EGFR ligands, TGF-α or HB-EGF, also decreased GRP-mediated MAPK activation. On matrix metalloproteinase (MMP) inhibition, GRP failed to activate MAPK in NSCLC cells. EGF and GRP both stimulated NSCLC proliferation, and inhibition of either EGFR or GRPR resulted in cell death. Combining a GRPR antagonist with the EGFR tyrosine kinase inhibitor, gefitinib, resulted in additive cytotoxic effects. Additive effects were seen at gefitinib concentrations from 1 to 18 μM, encompassing the ID50 values of both gefitinib-sensitive and gefitinib-resistant NSCLC cell lines. Because a major effect of GRPR appears to be promoting the release of EGFR ligand, this study suggests that a greater inhibition of cell proliferation may occur by abrogating EGFR ligand release in consort with inhibition of EGFR.",

keywords = "EGFR, GRPR, MAPK, Non-small cell lung cancer, Signal transduction",

author = "Thomas, {Sufi Mary} and Grandis, {Jennifer Rubin} and Wentzel, {Abbey L.} and Gooding, {William E.} and Lui, {Vivian Wai Yan} and Siegfried, {Jill M.}",

note = "Funding Information: Address all correspondence to: Jill M. Siegfried, PhD, Department of Pharmacology, University of Pittsburgh, E1340, 200 Lothrop Street, Pittsburgh, PA 15213. E-mail: [email protected] 1This work was supported by a grant (U01 CA84968) from the Early Detection Research Network (J.R.G. and J.M.S.), a grant (P50 CA90440) from the Specialized Program of Research Excellence (J.M.S.), and a National Institutes of Health grant (1 R01 CA 098372-01). S.M.T. and V.Y.W.L. were supported by Career Development Awards from the University of Pittsburgh Lung Cancer SPORE. Received 30 June 2004; Revised 1 November 2004; Accepted 3 November 2004.",

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doi = "10.1593/neo.04454",

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AU - Thomas, Sufi Mary

AU - Grandis, Jennifer Rubin

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AU - Gooding, William E.

AU - Lui, Vivian Wai Yan

AU - Siegfried, Jill M.

N1 - Funding Information: Address all correspondence to: Jill M. Siegfried, PhD, Department of Pharmacology, University of Pittsburgh, E1340, 200 Lothrop Street, Pittsburgh, PA 15213. E-mail: [email protected] 1This work was supported by a grant (U01 CA84968) from the Early Detection Research Network (J.R.G. and J.M.S.), a grant (P50 CA90440) from the Specialized Program of Research Excellence (J.M.S.), and a National Institutes of Health grant (1 R01 CA 098372-01). S.M.T. and V.Y.W.L. were supported by Career Development Awards from the University of Pittsburgh Lung Cancer SPORE. Received 30 June 2004; Revised 1 November 2004; Accepted 3 November 2004.

PY - 2005/4

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N2 - Gastrin-releasing peptide receptor (GRPR) and the epidermal growth factor receptor (EGFR) are expressed in several cancers including non-small cell lung cancer (NSCLC). Here we demonstrate the activation of EGFR by the GRPR ligand, gastrin-releasing peptide (GRP), in NSCLC cells. GRP induced rapid activation of p44/42 MAPK in lung cancer cells through EGFR. GRP-mediated activation of MAPK in NSCLC cells was abrogated by pretreatment with the anti-EGFR-neutralizing antibody, C225. Pretreatment of NSCLC cells with neutralizing antibodies to the EGFR ligands, TGF-α or HB-EGF, also decreased GRP-mediated MAPK activation. On matrix metalloproteinase (MMP) inhibition, GRP failed to activate MAPK in NSCLC cells. EGF and GRP both stimulated NSCLC proliferation, and inhibition of either EGFR or GRPR resulted in cell death. Combining a GRPR antagonist with the EGFR tyrosine kinase inhibitor, gefitinib, resulted in additive cytotoxic effects. Additive effects were seen at gefitinib concentrations from 1 to 18 μM, encompassing the ID50 values of both gefitinib-sensitive and gefitinib-resistant NSCLC cell lines. Because a major effect of GRPR appears to be promoting the release of EGFR ligand, this study suggests that a greater inhibition of cell proliferation may occur by abrogating EGFR ligand release in consort with inhibition of EGFR.

AB - Gastrin-releasing peptide receptor (GRPR) and the epidermal growth factor receptor (EGFR) are expressed in several cancers including non-small cell lung cancer (NSCLC). Here we demonstrate the activation of EGFR by the GRPR ligand, gastrin-releasing peptide (GRP), in NSCLC cells. GRP induced rapid activation of p44/42 MAPK in lung cancer cells through EGFR. GRP-mediated activation of MAPK in NSCLC cells was abrogated by pretreatment with the anti-EGFR-neutralizing antibody, C225. Pretreatment of NSCLC cells with neutralizing antibodies to the EGFR ligands, TGF-α or HB-EGF, also decreased GRP-mediated MAPK activation. On matrix metalloproteinase (MMP) inhibition, GRP failed to activate MAPK in NSCLC cells. EGF and GRP both stimulated NSCLC proliferation, and inhibition of either EGFR or GRPR resulted in cell death. Combining a GRPR antagonist with the EGFR tyrosine kinase inhibitor, gefitinib, resulted in additive cytotoxic effects. Additive effects were seen at gefitinib concentrations from 1 to 18 μM, encompassing the ID50 values of both gefitinib-sensitive and gefitinib-resistant NSCLC cell lines. Because a major effect of GRPR appears to be promoting the release of EGFR ligand, this study suggests that a greater inhibition of cell proliferation may occur by abrogating EGFR ligand release in consort with inhibition of EGFR.

KW - EGFR

KW - GRPR

KW - MAPK

KW - Non-small cell lung cancer

KW - Signal transduction

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Gastrin-releasing peptide receptor mediates activation of the epidermal growth factor receptor in lung cancer cells

Abstract

Bibliographical note

Keywords

UN SDGs

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