Lysophosphatidic acid decreases epidermal growth factor receptor binding in airway epithelial cells

Karen M. Kassel, Nancy A. Schulte, Stacey M. Parker, Aaron D. Lanik, Myron Lee Toews

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

We showed previously that treatment of human airway smooth muscle cells and lung fibroblasts with lysophosphatidic acid (LPA) increases the binding of epidermal growth factor (EGF) to EGF receptors (EGFRs). The purpose of this study was to determine whether LPA also regulates EGFR binding in airway epithelial cells. Airway epithelial cells were incubated in the absence or presence of 10 μM LPA for increasing times, and binding of 125I-EGF to intact cells on ice was measured. Exposure to LPA for only 15 min caused a 30 to 70% decrease in EGFR binding in a dose-dependent manner, depending on the cell line. This decrease in binding was sustained to at least 18 h in BEAS-2B and primary human bronchial epithelial cells. In contrast, the LPA-induced decrease in binding reversed rapidly in two lung cancer epithelial cell lines, H292 and A549, returning to control levels within 3 h. LPA increased phosphorylation of the EGFR in BEAS-2B cells, and this phosphorylation was inhibited by both 4-(3′-chloroanilino)-6,7-dimethoxy- quinazoline (AG1478; EGFR tyrosine kinase inhibitor) and N-[(2R)-2- (hydroxamidocarbonylmethyl)-4-methylpentanoyl]-L-tryptophan methylamide (GM6001; matrix metalloproteinase inhibitor) but not by CRM197 (heparin-binding EGF inhibitor). AG-1478 and GM6001 also inhibited the LPA-induced decrease in EGFR binding but only by 50%, suggesting only partial involvement of EGFR transactivation in the decrease in EGFR binding. In summary, LPA stimulates a decrease in EGFR binding in airway epithelial cells that is sustained in normal cells but that rapidly reverses in cancer cells. LPA-induced transactivation of EGFRs occurs and contributes to the decrease in EGFR binding, but additional pathway(s) may also be involved.

Original languageEnglish (US)
Pages (from-to)109-118
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume323
Issue number1
DOIs
StatePublished - Oct 1 2007

Fingerprint

Epidermal Growth Factor Receptor
Epithelial Cells
Epidermal Growth Factor
Transcriptional Activation
lysophosphatidic acid
ErbB Receptors
Phosphorylation
Quinazolines
Cell Line
Matrix Metalloproteinase Inhibitors
Ice
Tryptophan
Protein-Tyrosine Kinases
Smooth Muscle Myocytes
Heparin
Lung Neoplasms
Fibroblasts
Lung

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

Lysophosphatidic acid decreases epidermal growth factor receptor binding in airway epithelial cells. / Kassel, Karen M.; Schulte, Nancy A.; Parker, Stacey M.; Lanik, Aaron D.; Toews, Myron Lee.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 323, No. 1, 01.10.2007, p. 109-118.

Research output: Contribution to journalArticle

Kassel, Karen M. ; Schulte, Nancy A. ; Parker, Stacey M. ; Lanik, Aaron D. ; Toews, Myron Lee. / Lysophosphatidic acid decreases epidermal growth factor receptor binding in airway epithelial cells. In: Journal of Pharmacology and Experimental Therapeutics. 2007 ; Vol. 323, No. 1. pp. 109-118.
@article{e97b9037312e4def8cc137aa63396eac,
title = "Lysophosphatidic acid decreases epidermal growth factor receptor binding in airway epithelial cells",
abstract = "We showed previously that treatment of human airway smooth muscle cells and lung fibroblasts with lysophosphatidic acid (LPA) increases the binding of epidermal growth factor (EGF) to EGF receptors (EGFRs). The purpose of this study was to determine whether LPA also regulates EGFR binding in airway epithelial cells. Airway epithelial cells were incubated in the absence or presence of 10 μM LPA for increasing times, and binding of 125I-EGF to intact cells on ice was measured. Exposure to LPA for only 15 min caused a 30 to 70{\%} decrease in EGFR binding in a dose-dependent manner, depending on the cell line. This decrease in binding was sustained to at least 18 h in BEAS-2B and primary human bronchial epithelial cells. In contrast, the LPA-induced decrease in binding reversed rapidly in two lung cancer epithelial cell lines, H292 and A549, returning to control levels within 3 h. LPA increased phosphorylation of the EGFR in BEAS-2B cells, and this phosphorylation was inhibited by both 4-(3′-chloroanilino)-6,7-dimethoxy- quinazoline (AG1478; EGFR tyrosine kinase inhibitor) and N-[(2R)-2- (hydroxamidocarbonylmethyl)-4-methylpentanoyl]-L-tryptophan methylamide (GM6001; matrix metalloproteinase inhibitor) but not by CRM197 (heparin-binding EGF inhibitor). AG-1478 and GM6001 also inhibited the LPA-induced decrease in EGFR binding but only by 50{\%}, suggesting only partial involvement of EGFR transactivation in the decrease in EGFR binding. In summary, LPA stimulates a decrease in EGFR binding in airway epithelial cells that is sustained in normal cells but that rapidly reverses in cancer cells. LPA-induced transactivation of EGFRs occurs and contributes to the decrease in EGFR binding, but additional pathway(s) may also be involved.",
author = "Kassel, {Karen M.} and Schulte, {Nancy A.} and Parker, {Stacey M.} and Lanik, {Aaron D.} and Toews, {Myron Lee}",
year = "2007",
month = "10",
day = "1",
doi = "10.1124/jpet.107.120584",
language = "English (US)",
volume = "323",
pages = "109--118",
journal = "Journal of Pharmacology and Experimental Therapeutics",
issn = "0022-3565",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "1",

}

TY - JOUR

T1 - Lysophosphatidic acid decreases epidermal growth factor receptor binding in airway epithelial cells

AU - Kassel, Karen M.

AU - Schulte, Nancy A.

AU - Parker, Stacey M.

AU - Lanik, Aaron D.

AU - Toews, Myron Lee

PY - 2007/10/1

Y1 - 2007/10/1

N2 - We showed previously that treatment of human airway smooth muscle cells and lung fibroblasts with lysophosphatidic acid (LPA) increases the binding of epidermal growth factor (EGF) to EGF receptors (EGFRs). The purpose of this study was to determine whether LPA also regulates EGFR binding in airway epithelial cells. Airway epithelial cells were incubated in the absence or presence of 10 μM LPA for increasing times, and binding of 125I-EGF to intact cells on ice was measured. Exposure to LPA for only 15 min caused a 30 to 70% decrease in EGFR binding in a dose-dependent manner, depending on the cell line. This decrease in binding was sustained to at least 18 h in BEAS-2B and primary human bronchial epithelial cells. In contrast, the LPA-induced decrease in binding reversed rapidly in two lung cancer epithelial cell lines, H292 and A549, returning to control levels within 3 h. LPA increased phosphorylation of the EGFR in BEAS-2B cells, and this phosphorylation was inhibited by both 4-(3′-chloroanilino)-6,7-dimethoxy- quinazoline (AG1478; EGFR tyrosine kinase inhibitor) and N-[(2R)-2- (hydroxamidocarbonylmethyl)-4-methylpentanoyl]-L-tryptophan methylamide (GM6001; matrix metalloproteinase inhibitor) but not by CRM197 (heparin-binding EGF inhibitor). AG-1478 and GM6001 also inhibited the LPA-induced decrease in EGFR binding but only by 50%, suggesting only partial involvement of EGFR transactivation in the decrease in EGFR binding. In summary, LPA stimulates a decrease in EGFR binding in airway epithelial cells that is sustained in normal cells but that rapidly reverses in cancer cells. LPA-induced transactivation of EGFRs occurs and contributes to the decrease in EGFR binding, but additional pathway(s) may also be involved.

AB - We showed previously that treatment of human airway smooth muscle cells and lung fibroblasts with lysophosphatidic acid (LPA) increases the binding of epidermal growth factor (EGF) to EGF receptors (EGFRs). The purpose of this study was to determine whether LPA also regulates EGFR binding in airway epithelial cells. Airway epithelial cells were incubated in the absence or presence of 10 μM LPA for increasing times, and binding of 125I-EGF to intact cells on ice was measured. Exposure to LPA for only 15 min caused a 30 to 70% decrease in EGFR binding in a dose-dependent manner, depending on the cell line. This decrease in binding was sustained to at least 18 h in BEAS-2B and primary human bronchial epithelial cells. In contrast, the LPA-induced decrease in binding reversed rapidly in two lung cancer epithelial cell lines, H292 and A549, returning to control levels within 3 h. LPA increased phosphorylation of the EGFR in BEAS-2B cells, and this phosphorylation was inhibited by both 4-(3′-chloroanilino)-6,7-dimethoxy- quinazoline (AG1478; EGFR tyrosine kinase inhibitor) and N-[(2R)-2- (hydroxamidocarbonylmethyl)-4-methylpentanoyl]-L-tryptophan methylamide (GM6001; matrix metalloproteinase inhibitor) but not by CRM197 (heparin-binding EGF inhibitor). AG-1478 and GM6001 also inhibited the LPA-induced decrease in EGFR binding but only by 50%, suggesting only partial involvement of EGFR transactivation in the decrease in EGFR binding. In summary, LPA stimulates a decrease in EGFR binding in airway epithelial cells that is sustained in normal cells but that rapidly reverses in cancer cells. LPA-induced transactivation of EGFRs occurs and contributes to the decrease in EGFR binding, but additional pathway(s) may also be involved.

UR - http://www.scopus.com/inward/record.url?scp=34548845373&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34548845373&partnerID=8YFLogxK

U2 - 10.1124/jpet.107.120584

DO - 10.1124/jpet.107.120584

M3 - Article

VL - 323

SP - 109

EP - 118

JO - Journal of Pharmacology and Experimental Therapeutics

JF - Journal of Pharmacology and Experimental Therapeutics

SN - 0022-3565

IS - 1

ER -