GSBS Student Publications

Title

Identification of ATF-3, caveolin-1, DLC-1, and NM23-H2 as putative antitumorigenic, progesterone-regulated genes for ovarian cancer cells by gene profiling

UMMS Affiliation

Graduate School of Biomedical Sciences; Department of Surgery; Department of Biochemistry and Molecular Pharmacology

Date

1-28-2005

Document Type

Article

Medical Subject Headings

Activating Transcription Factor 3; Caspase 3; Caspases; Caveolin 3; Caveolins; Enzyme Activation; Female; Gene Expression Profiling; Genes, Tumor Suppressor; Humans; NM23 Nucleoside Diphosphate Kinases; Nucleoside-Diphosphate Kinase; Ovarian Neoplasms; Progesterone; RNA, Messenger; Transcription Factors; Tumor Suppressor Proteins

Disciplines

Life Sciences | Medicine and Health Sciences

Abstract

Although progesterone (P4) has been implicated to offer protection against ovarian cancer (OCa), little is known of its mechanism of action. The goal of this study was to identify P4-regulated genes that have anti-OCa action. Three immortalized nontumorigenic human ovarian surface epithelial (HOSE) cell lines and three OCa (OVCA) cell lines were subjected to 5 days of P4 treatment. Transcriptional profiling with a cDNA microarray containing approximately 2400 known genes was used to identify genes (1) whose expression was consistently downregulated in OVCA cell lines compared to HOSE cell lines, and (2) whose expression was restored in OCa cell lines by P4 treatment. From the candidates selected, activating transcription factor-3 (ATF-3), caveolin-1, deleted in liver cancer-1 (DLC-1), and nonmetastatic clone 23 (NM23-H2) were chosen for post hoc functional studies based on their previously reported action as tumor suppressors or apoptosis inducers. Semiquantitative RT-PCR analyses confirmed loss of or reduced transcription of these genes in OVCA cells when compared to HOSE cells and their upregulation following P4 treatment. Hormonal specificity was demonstrated by blockade experiments with a progestin antagonist RU 38486. Ectopic expression of caveolin-1, DLC-1, and NM23-H2 caused growth inhibition in OVCA cell cultures, but not in HOSE cell cultures, while forced expression of ATF-3 suppressed growth in both. Overexpression of AFT-3 also enhanced caspase-3 activity in both HOSE and OVCA cells, whereas ectopic expression of caveolin-1 and DLC-1 only activated this enzyme in OCa cells. In contrast, NM23-H2 overexpression was ineffective in activating caspase-3. Overexpression of any of the four genes in OCa cells reduced soft-agar colony formation and cell invasiveness. Taken together, we have identified four new P4-regulated, antitumor genes for OCa. However, their modes of action differ significantly; ATF-3 primarily functions as an apoptosis inducer, NM23-H2 as a suppressor of cell motility, and caveolin-1 and DLC-1 exhibiting features of classical tumor suppressors. To the best of our knowledge, except for NM23-H2, this is the first report linking P4 to the regulation of these tumor suppressor/proapoptotic genes, which could serve as future therapeutic targets.

Rights and Permissions

Citation: Oncogene. 2005 Mar 3;24(10):1774-87. Link to article on publisher's site

DOI of Published Version

10.1038/sj.onc.1207991

Related Resources

Link to Article in PubMed

Journal Title

Oncogene

PubMed ID

15674352