This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kim, H.-J. Articles by Farrar, W. L. Search for Related Content PubMed PubMed Citation Articles by Kim, H.-J. Articles by Farrar, W. L.

15-Deoxy-^12,14-Prostaglandin J₂ Inhibits Transcriptional Activity of Estrogen Receptor- via Covalent Modification of DNA-Binding Domain

¹ Cancer Stem Cell Section, Laboratory of Cancer Prevention, ² Laboratory of Proteomics and Analytical Technologies; and ³ Basic Research Program, Science Applications International Corporation-Frederick and ⁴ Laboratory of Medicinal Chemistry, Center for Cancer Research, National Cancer Institute, Frederick, Maryland

Requests for reprints: William L. Farrar, Laboratory of Cancer Prevention, National Cancer Institute-Frederick, Room 21–81, Building 560, 1050 Boyles Street, Frederick, MD 21702. Phone: 310-846-1503; Fax: 301-846-6019; E-mail: farrar{at}mail.ncifcrf.gov.

The cyclopentenone 15-deoxy-^12,14-prostaglandin J₂ (15d-PGJ₂) inhibits proliferation of cancer cells, including breast cancers, by peroxisome proliferator-activated receptor- (PPAR)–dependent and PPAR-independent mechanisms. However, little is known about its effect on the transcriptional activity of estrogen receptor- (ER) that plays vital roles in the growth of breast cancers. Here, we show that 15d-PGJ₂ inhibits both 17ß-estradiol (E₂)–dependent and E₂-independent ER transcriptional activity by PPAR-independent mechanism. In addition, 15d-PGJ₂ directly modifies ER protein via its reactive cyclopentenone moiety, evidenced by incorporation of biotinylated 15d-PGJ₂ into ER, both in vitro and in vivo. Nanoflow reverse-phase liquid chromatography tandem mass spectrometry analysis identifies two cysteines (Cys²²⁷ and Cys²⁴⁰) within the COOH-terminal zinc finger of ER DNA-binding domain (DBD) as targets for covalent modification by 15d-PGJ₂. Gel mobility shift and chromatin immunoprecipitation assays show that 15d-PGJ₂ inhibits DNA binding of ER and subsequent repression of ER target gene expression, such as pS2 and c-Myc. Therefore, our results suggest that 15d-PGJ₂ can block ER function by covalent modification of cysteine residues within the vulnerable COOH-terminal zinc finger of ER DBD, resulting in fundamental inhibition of both hormone-dependent and hormone-independent ER transcriptional activity. [Cancer Res 2007;67(6):2595–602]

This article has been cited by other articles:

				A. J. Ryan, B. B. Chen, P. R. Vennalaganti, F. C. Henderson, L. A. Tephly, A. B. Carter, and R. K. Mallampalli 15-Deoxy-{Delta}12,14-prostaglandin J2 Impairs Phosphatidylcholine Synthesis and Induces Nuclear Accumulation of Thiol-modified Cytidylyltransferase J. Biol. Chem., September 5, 2008; 283(36): 24628 - 24640. [Abstract] [Full Text] [PDF]

				H. J. Yoon, S.-B. Jeon, I.-H. Kim, and E. J. Park Regulation of TLR2 Expression by Prostaglandins in Brain Glia J. Immunol., June 15, 2008; 180(12): 8400 - 8409. [Abstract] [Full Text] [PDF]

				R. Ahmad, D. Raina, C. Meyer, and D. Kufe Triterpenoid CDDO-Methyl Ester Inhibits the Janus-Activated Kinase-1 (JAK1)->Signal Transducer and Activator of Transcription-3 (STAT3) Pathway by Direct Inhibition of JAK1 and STAT3 Cancer Res., April 15, 2008; 68(8): 2920 - 2926. [Abstract] [Full Text] [PDF]