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Mol. Hum. Reprod. Advance Access published online on September 23, 2007
Molecular Human Reproduction, doi:10.1093/molehr/gam071
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© The Author 2007. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Growth inhibition and apoptosis induced in human leiomyoma cells by treatment with the PPAR gamma ligand ciglitizone

Dong-Ho Nam, MD1,*, Sabarish Ramachandran, MS1,*, Dae-Kyu Song, MD2, Kun-Young Kwon, MD3, Dong-Seok Jeon, MD4, So-Jin Shin, MD1, Sang-Hoon Kwon, MD1, Soon-Do Cha, MD1, Insoo Bae, PhD5 and Chi-Heum Cho, MD1,{dagger}

1Department of Obstetrics and Gynecology 2Department of Physiology 3Department of Pathology 4Department of Laboratory Medicine, School of Medicine, Keimyung University, Daegu, Korea 5Department of Oncology, Lombardi Cancer Center, Georgetown University, 3970 Reservoir Road, NW, Washington, DC 20007, USA

{dagger} To whom correspondence should be addressed: Chi-heum Cho M.D. Department of Obstetrics and Gynecology, Keimyung University, School of Medicine, 194 Dongsan-Dong, Jung-Ku, Daegu, 700-712 Korea, Tel: 82-53-250-7518; Fax: 82-53-250-7599; E-mail: chcho{at}kmu.ac.kr

The nuclear receptors PPARs (peroxisome proliferator-activated receptors) are transcription factors that play important roles in multiple disease conditions. The activation of PPARs by specific ligands is associated with growth suppression of several different types of human cancer, but the molecular mechanism responsible for this growth suppressive effect remains elusive. The aim of this study was to determine the distribution of PPAR{gamma} protein/mRNA expression in uterine leiomyomas and to identify the PPAR{gamma} induced signalling pathways responsible for the growth inhibition induced by treatment with ciglitizone, a synthetic ligand of PPAR{gamma}, in view of identifying targets that could possibly affect the viability and proliferation of uterine leiomyoma cells. Dose-response studies on proliferation found that uterine leiomyoma was more sensitive to inhibition by ciglitizone treatments than normal myometrium. We also found that ciglitizone significantly stimulated gene expression driven by a PPAR-responsive element in cultured leiomyoma cells and reduced the survival of leiomyoma cells relative to the control cells. The reduced survival of ciglitizone treated leiomyoma cells resulted from a mechanism that involved the FAS receptor-mediated apoptosis signalling cascade. These results suggest that uterine leiomyomas growth and differentiation might be modulated through PPAR{gamma} receptors and that PPAR{gamma} ligands may be of potential use for uterine leiomyoma treatment.

Key Words: Uterine leiomyoma/PPAR{gamma}/Ciglitizone/Apoptosis

* These two authors have made equal contributions to the manuscript

Submitted on August 17, 2007; resubmitted on September 7, 2007; accepted on September 20, 2007.


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S.-H. Kwon, J.-C. Park, S. Ramachandran, S.-D. Cha, K.-Y. Kwon, J.-K. Park, J.-W. Park, I. Bae, and C.-H. Cho
Loss of Cyclin G1 Expression in Human Uterine Leiomyoma Cells Induces Apoptosis
Reproductive Sciences, April 1, 2008; 15(4): 400 - 410.
[Abstract] [PDF]


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