University of Groningen Anticancer Effects of 15d-Prostaglandin-J(2) in Wild-Type and Doxorubicin-Resistant Ovarian Cancer Cells

15-deoxy-delta-12,14-prostaglandin-J2 (15d-PGJ2), an arachidonic metabolite and a natural PPARc agonist, is known to induce apoptosis in tumor cells. In this study, we investigated new therapeutic potentials of 15d-PGJ2 by determining its anticancer effects in wild-type and doxorubicin-resistant ovarian carcinoma cells. Despite high expression of resistanceinducing genes like MDR1, Bcl2 and Bcl-xl, 15d-PGJ2 strongly induced apoptosis in doxorubicin-resistant (A2780/AD) cells similar to the wild-type (A2780). This was found to be related to caspase-3/7and NF-kB pathways but not to its PPARc agonistic activity. 15d-PGJ2 also was able to reduce the doxorubicin resistance of A2780/AD cells at low doses as confirmed by the inhibition of gene expression of MDR1 (p-glycoprotein) and SIRT1 (a drug senescence gene). We also investigated effects of 15d-PGJ2 on cell migration and transformation using a wound-healing assay and morphological analyses, respectively. We found that 15d-PGJ2 inhibited migration most likely due to NF-kB inhibition and induced transformation of the round-shape A2780/AD cells into elongated epithelial cells due to HDAC1 inhibition. Using a 15d-PGJ2 analog, we found the mechanism of action of these new activities of 15d-PGJ2 on SIRT1 and HDAC1 gene expressions and enzyme activities. In conclusion, the present study demonstrates that 15d-PGJ2 has a high therapeutic potential to kill drug-resistant tumor cells and, the newly described inhibitory effects of this cyclo-oxygenase product on SIRT1 and HDAC will provide new opportunities for cancer therapeutics. Citation: de Jong E, Winkel P, Poelstra K, Prakash J (2011) Anticancer Effects of 15d-Prostaglandin-J2 in Wild-Type and Doxorubicin-Resistant Ovarian Cancer Cells: Novel Actions on SIRT1 and HDAC. PLoS ONE 6(9): e25192. doi:10.1371/journal.pone.0025192 Editor: Olivier Gires, Ludwig-Maximilians University, Germany Received April 26, 2011; Accepted August 29, 2011; Published September 21, 2011 Copyright: 2011 de Jong et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This study was supported by European Union project of Innovative Action Program Groningen, The Netherlands, and by a Vici grant from the Dutch Technical Foundation (STW). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: jai.prakash@ki.se . These authors contributed equally to this work. ¤ Current address: Department of Oncology-Pathology, Cancer Centre Karolinska, Karolinska Institutet, Stockholm, Sweden

[1]  M. McNutt,et al.  SIRT1 is regulated by a PPARγ–SIRT1 negative feedback loop associated with senescence , 2010, Nucleic acids research.

[2]  M. Horinaka,et al.  Histone Deacetylase Inhibitors and 15-Deoxy-Δ12,14-Prostaglandin J2 Synergistically Induce Apoptosis , 2010, Clinical Cancer Research.

[3]  J. Kwak,et al.  15d-PGJ2 Induces Apoptosis by Reactive Oxygen Species–mediated Inactivation of Akt in Leukemia and Colorectal Cancer Cells and Shows In vivo Antitumor Activity , 2009, Clinical Cancer Research.

[4]  H. Verheul,et al.  Understanding the causes of multidrug resistance in cancer: a comparison of doxorubicin and sunitinib. , 2009, Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy.

[5]  G. Marshall,et al.  The critical role of the class III histone deacetylase SIRT1 in cancer. , 2009, Cancer research.

[6]  H. Höfler,et al.  The E-cadherin repressor Snail is associated with lower overall survival of ovarian cancer patients , 2007, British Journal of Cancer.

[7]  Y. Surh,et al.  15 -Deoxy -Δ12,14 -prostaglandin J2 as a potential endogenous regulator of redox-sensitive transcription factors , 2006 .

[8]  O. Sezer,et al.  Peroxisome proliferator-activated receptor-gamma ligands inhibit proliferation and induce apoptosis in mantle cell lymphoma , 2006, Anti-cancer drugs.

[9]  A. Rebbaa,et al.  Control of multidrug resistance gene mdr1 and cancer resistance to chemotherapy by the longevity gene sirt1. , 2005, Cancer research.

[10]  Alan Richardson,et al.  Drug resistance in ovarian cancer: the emerging importance of gene transcription and spatio-temporal regulation of resistance. , 2005, Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy.

[11]  J. Nesland,et al.  Snail, Slug, and Smad‐interacting protein 1 as novel parameters of disease aggressiveness in metastatic ovarian and breast carcinoma , 2005, Cancer.

[12]  M. Mayo,et al.  Modulation of NF‐κB‐dependent transcription and cell survival by the SIRT1 deacetylase , 2004, The EMBO journal.

[13]  H. Nakshatri,et al.  NF-κ B Promotes Breast Cancer Cell Migration and Metastasis by Inducing the Expression of the Chemokine Receptor CXCR4* , 2003, Journal of Biological Chemistry.

[14]  E. Hammond,et al.  Cell cycle blockade and differentiation of ovarian cancer cells by the histone deacetylase inhibitor trichostatin A are associated with changes in p21, Rb, and Id proteins. , 2002, Molecular cancer therapeutics.

[15]  C. Glass,et al.  15-deoxy-delta 12,14-prostaglandin J2 inhibits multiple steps in the NF-kappa B signaling pathway. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[16]  Marty W. Mayo,et al.  NF-κB Induces Expression of the Bcl-2 Homologue A1/Bfl-1 To Preferentially Suppress Chemotherapy-Induced Apoptosis , 1999, Molecular and Cellular Biology.

[17]  J. Lehmann,et al.  The structure - Activity relationship between peroxisome proliferator-activated receptor γ agonism and the antihyperglycemic activity of thiazolidinediones , 1996 .

[18]  W. Smith Prostanoid biosynthesis and mechanisms of action. , 1992, The American journal of physiology.

[19]  Ruchi Bansal,et al.  Albumin-binding and tumor vasculature determine the antitumor effect of 15-deoxy-Delta-(12,14)-prostaglandin-J(2) in vivo. , 2009, Neoplasia.

[20]  S. K. Kang,et al.  15-deoxy-(Delta12,14)-prostaglandin J2 (15d-PGJ2) induces cell death through caspase-independent mechanism in A172 human glioma cells. , 2006, Neurochemical research.

[21]  K. Itoh,et al.  Transcription factor Nrf2 regulates inflammation by mediating the effect of 15-deoxy-Delta(12,14)-prostaglandin j(2). , 2004, Molecular and cellular biology.

[22]  W. Koenig,et al.  Activation of human aortic smooth-muscle cells is inhibited by PPARalpha but not by PPARgamma activators. , 1998, Nature.