Growth hormone-releasing hormone antagonist induces apoptosis of human endometrial cancer cells through PKCδ-mediated activation of p53/p21

Hsien-Ming Wu; Andrew V Schally; Jung-Chien Cheng; Marta Zarandi; Jozsef Varga; Peter C K Leung

doi:10.1016/j.canlet.2010.05.022

Growth hormone-releasing hormone antagonist induces apoptosis of human endometrial cancer cells through PKCδ-mediated activation of p53/p21

Cancer Lett. 2010 Dec 1;298(1):16-25. doi: 10.1016/j.canlet.2010.05.022. Epub 2010 Jul 13.

Authors

Hsien-Ming Wu¹, Andrew V Schally, Jung-Chien Cheng, Marta Zarandi, Jozsef Varga, Peter C K Leung

Affiliation

¹ Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, British Columbia, Canada V6H3V5.

PMID: 20630651
DOI: 10.1016/j.canlet.2010.05.022

Abstract

The growth hormone-releasing hormone (GHRH) antagonists have been shown to inhibit growth of human cancer cells, but the underlying molecular mechanisms and their actions have not been fully investigated. In this study, we first showed that GHRH-R splice variant 1 (SV1) was expressed in two human endometrial cancer cell lines, Ishikawa and ECC-1. By using MTT assay, immunoblotting for cleaved caspase-3 and TUNEL assays, we found that cell growth inhibition and apoptosis were induced in GHRH antagonist, JMR-132-treated cells by activating PKCδ and could be inhibited by treatment with PKC inhibitor, GF109203X. In addition, activation and protein expression of p53 as well as the expression of its downstream effector, p21, were increased by JMR-132 treatment. Moreover, JMR-132-induced p53 and p21 expression were diminished by treatment with PKC inhibitor. Knockdown of endogenous p53 and p21 by siRNAs abolished the JMR-132-induced cell growth inhibition and apoptosis. This study demonstrates a novel mechanism in which GHRH antagonist-induced cell growth inhibition and apoptosis through PKCδ-mediated activation of p53/p21 in human endometrial cancer cells. These findings may suggest the feasibility of GHRH antagonists as a therapeutic approach for human cancer.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Apoptosis / drug effects*
Cell Line, Tumor
Cell Survival / drug effects
Cyclin-Dependent Kinase Inhibitor p21 / biosynthesis*
Cyclin-Dependent Kinase Inhibitor p21 / genetics
Cyclin-Dependent Kinase Inhibitor p21 / metabolism
Endometrial Neoplasms / drug therapy*
Endometrial Neoplasms / genetics
Endometrial Neoplasms / metabolism
Endometrial Neoplasms / pathology
Female
Gene Knockdown Techniques
Growth Hormone-Releasing Hormone / antagonists & inhibitors*
Growth Hormone-Releasing Hormone / metabolism
Humans
Indoles / pharmacology
Maleimides / pharmacology
Protein Isoforms
Protein Kinase C-delta / antagonists & inhibitors
Protein Kinase C-delta / biosynthesis*
Protein Kinase C-delta / genetics
Protein Kinase C-delta / metabolism
RNA, Messenger / biosynthesis
RNA, Messenger / genetics
RNA, Small Interfering / genetics
Sermorelin / analogs & derivatives*
Sermorelin / pharmacology
Tumor Suppressor Protein p53 / metabolism*

Substances

CDKN1A protein, human
Cyclin-Dependent Kinase Inhibitor p21
GHRH(1-29)NH2, PhAcTyr(1)-Arg(2)-P(H)e(4-CL)(6)-Ala(8)-Tyr(Me)(10)-His(11)-Abu(15)-His(20)-Nle(27)-Arg(28)-HLCr(29)-
Indoles
Maleimides
Protein Isoforms
RNA, Messenger
RNA, Small Interfering
TP53 protein, human
Tumor Suppressor Protein p53
Sermorelin
Growth Hormone-Releasing Hormone
Protein Kinase C-delta
bisindolylmaleimide I