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This Article Accepted manuscript (PDF) All Versions of this Article: JME-09-0121v1 44/2/127    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Barabutis, N. Articles by Varga, J. PubMed PubMed Citation Articles by Barabutis, N. Articles by Varga, J.

N Barabutis, Pathology, University of Miami, Miami, 33125, United States
A Siejka, Hematology, University of Miami, Miami, United States
A Schally, research 151, Veterans Affairs Medical Center, Miami, United States
N Block, Pathology/Hematology/Oncology/Endocrinology, University of Miami, Miami, United States
R Cai, Pathology, University of Miami, Miami, United States
J Varga, Hematology, University of Miami, Miami, United States

Correspondence: Nektarios Barabutis, Email: nbarabutis{at}gmail.com

Abstract

Hypothalamic Growth Hormone Releasing Hormone (GHRH) controls the release of Growth Hormone from the pituitary gland and also acts as a growth factor in a variety of cancers. The mitogenetic activity of GHRH is exerted through the binding to the pituitary type receptors (pGHRH-R) and its splice variants, mainly SV1. The intracellular signaling pathways which are activated upon the binding of GHRH to the SV1 receptor have not been elucidated. HeLa cervical cancer cells do not express GHRH or GHRH receptors, and thus do not respond to GHRH or GHRH antagonists. In order to elucidate the mechanism of action of SV1 receptor, we transfected HeLa cells with plasmids for pcDNA3GHRHR or pcDNA3SV1. The transfected cells responded to both GHRH (1-29)NH2 and GHRH antagonist MZ-5-156, as shown by an increase or decrease, respectively, in the proliferation rate in vitro and the expression of proliferative cell nuclear antigen (PCNA). We also demonstrated that when the cells transfected with SV1 plasmid are stimulated with GHRH(1-29)NH2, SV1 receptor activates the Mitogen Activated Protein Kinases Pathway (MAPKs), as shown previously for the cells that express pGHRH-R. Our results show, for the first time, the activation of the MAPKs cascade by the SV1 receptor. Since SV1 receptor is found in various tumors and mediates the responses to GHRH and synthetic antagonists, our findings shed light on the mechanism of action of SV1 receptor in cancer cells.