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This Article Accepted manuscript (PDF) All Versions of this Article: JME-08-0106v1 41/5/389    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 Volakaki, A.-A. Articles by Kiaris, H. PubMed PubMed Citation Articles by Volakaki, A.-A. Articles by Kiaris, H.

A Volakaki, Athens, Greece
D Lafkas, Athens, Greece
E Kassi, Athens, Greece
A Schally, Miami, United States
A Papavassiliou, Athens, Greece
H Kiaris, Biochemistry, University of Athens Medical School, Athens, 11527, Greece

Correspondence: Hippokratis Kiaris, Email: hkiaris{at}med.uoa.gr

Abstract

Growth hormone-releasing hormone (GHRH), besides its neuroendocrine action in controlling the release of growth hormone from the pituitary, stimulates the growth of various cancers in vivo and in vitro by direct mechanism(s). However, the molecular mechanism that mediates these proliferative effects of GHRH in extrapituitary tissues remains poorly characterized. In the present study we investigated whether the tumor suppressor p21/waf1 is involved in the mediation of the proliferative effects of GHRH in A549 human lung cancer epithelial cells. Exposure of A549 cells to the GHRH antagonist JMR-132 caused a significant inhibition in the rate of cell proliferation. In A549 cells GHRH suppressed while JMR-132 increased the levels of p21 expression in a dose-dependent manner. This suggests that GHRH could regulate p21 levels. We then evaluated if p21 is required in A549 cells for the regulation of cell proliferation by GHRH. To this end, we knocked-down p21 expression in A549 cells by siRNA and assessed the effects of antagonist JMR-132 on cell proliferation. We found that the loss of p21 expression abolished the antiproliferative effects of JMR-132. Suppression of p21 expression by siRNA in human HT29 colon cancer cells and non-transformed mouse osteoblasts KS483 also blocked the antiproliferative effects of JMR-132 suggesting that the regulation of cell proliferation by GHRH is p21 dependent. These results shed light on the molecular mechanism of action of GHRH antagonists in tumor tissues, and suggest that the antineoplastic activity of GHRH antagonists could be considered for the treatment of cancers expressing p21