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A Combined 3D Tissue Engineered In Vitro/In Silico Lung Tumor Model for Predicting Drug Effectiveness in Specific Mutational Backgrounds
13:34

A Combined 3D Tissue Engineered In Vitro/In Silico Lung Tumor Model for Predicting Drug Effectiveness in Specific Mutational Backgrounds

Published on: April 6, 2016

A bombesin receptor subtype-3 peptide increases nuclear oncogene expression in a MEK-1 dependent manner in human lung

H C Weber1, J Walters, J Leyton

  • 1Section of Gastroenterology, Boston University School of Medicine, Boston, MA 02118, USA.

European Journal of Pharmacology
|February 13, 2001
PubMed

Insights

A synthetic peptide activates bombesin receptor subtype-3, leading to increased cytosolic calcium and mitogen-activated protein kinase (MAPK) phosphorylation in lung cancer cells. This pathway involves Elk-1 activation and upregulates oncogene expression, suggesting potential therapeutic targets.

Area of Science:

  • Molecular Biology
  • Cell Signaling
  • Oncology

Background:

  • Bombesin receptor subtype-3 (BRS-3) plays a role in cell proliferation and survival.
  • Understanding BRS-3 signaling is crucial for developing targeted cancer therapies.
  • Synthetic bombesin analogs are used to probe receptor function.

Purpose of the Study:

  • To investigate the signal transduction mechanisms of bombesin receptor subtype-3 (BRS-3).
  • To elucidate the downstream effects of BRS-3 activation by a synthetic peptide.
  • To identify key molecular events linking BRS-3 activation to oncogene expression.

Main Methods:

  • Utilized NCI-H1299#5 human lung cancer cells stably transfected with BRS-3.
  • Measured cytosolic calcium levels and mitogen-activated protein kinase (MAPK) phosphorylation.
  • Employed luciferase reporter gene assays for Elk-1 activation and quantified c-fos/c-jun mRNA levels.

Main Results:

  • The synthetic peptide (D-Phe(6), beta-Ala(11), Phe(13), Nle(14))bombesin-(6-14) rapidly elevated cytosolic Ca2+ and induced time- and concentration-dependent MAPK phosphorylation.
  • MAPK phosphorylation and subsequent Elk-1 activation were inhibited by PD98059 (a MAPK kinase inhibitor) and dominant-negative MEK-1.
  • The peptide significantly increased c-fos and c-jun mRNA expression, which was attenuated by PD98059, dominant-negative MEK-1, and a substance P antagonist.

Conclusions:

  • The synthetic peptide activates BRS-3, initiating a signaling cascade involving MAPK and Elk-1.
  • This activation leads to increased expression of oncogenes c-fos and c-jun in lung cancer cells.
  • The findings highlight the BRS-3/MAPK/Elk-1 pathway as a critical mediator of bombesin-induced oncogene expression.

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