RNA interference-directed silencing of VPAC1 receptor inhibits VIP effects on both EGFR and HER2 transactivation and VEGF secretion in human breast cancer cells.

Abstract

We used small-interference RNA (siRNA) to explore the mechanisms of some vasoactive intestinal peptide (VIP) actions on human breast cancer cells. Transfection of estrogen-dependent (T47D) and estrogen-independent (MDA-MB-468) breast cancer cells with VPAC(1)-receptor siRNA completely abolished VIP stimulatory effect on secretion of the main angiogenic factor, vascular endothelial growth factor (VEGF), and transactivation of epidermal growth factor receptor (EGFR or HER1) and HER2, two members of HER family of tyrosine-kinase receptors. The silencing procedure suggested the involvement of EGFR and HER2 transactivation in VIP-stimulated VEGF secretion. It was further supported by blocking tyrosine kinase activity by the selective HER inhibitors AG-1478 (EGFR) and AG-825 (HER2). Results give value to the specific signaling of VIP through VPAC(1) receptor in human breast cancer cells and support the potential use of VPAC(1)-receptor antagonists in combined targeted therapies for breast cancer. Molecular therapies involving RNA interference of VPAC(1)-receptor expression could also be considered.

• Authors: Ana Valdehita, María J Carmena, Ana M Bajo, Juan C Prieto
• Journal: Molecular and cellular endocrinology (Mol Cell Endocrinol) Vol. 348 Issue 1 Pg. 241-6 (Jan 02 2012) ISSN: 1872-8057 [Electronic] Ireland
• PMID: 21896307 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Protein Kinase Inhibitors
• Receptors, Vasoactive Intestinal Polypeptide, Type I
• VEGFA protein, human
• Vascular Endothelial Growth Factor A
• Vasoactive Intestinal Peptide
• ERBB2 protein, human
• ErbB Receptors
• Receptor, ErbB-2

Topics

• Breast Neoplasms
• Cell Line, Tumor
• Cell Proliferation
• ErbB Receptors (antagonists & inhibitors, genetics, metabolism)
• Gene Knockdown Techniques
• Humans
• Protein Kinase Inhibitors (pharmacology)
• RNA Interference
• Receptor, ErbB-2 (antagonists & inhibitors, genetics, metabolism)
• Receptors, Vasoactive Intestinal Polypeptide, Type I (genetics, metabolism)
• Transcriptional Activation
• Transfection
• Vascular Endothelial Growth Factor A (metabolism)
• Vasoactive Intestinal Peptide (metabolism)