title: Anticancer effects of 15d-prostaglandin-J2 in wild-type and doxorubicin-resistant ovarian cancer cells: novel actions on SIRT1 and HDAC.
abstract: 15-Deoxy-delta-12,14-prostaglandin-J(2) (15d-PGJ(2)), an arachidonic metabolite and a natural PPARγ agonist, is known to induce apoptosis in tumor cells. In this study, we investigated new therapeutic potentials of 15d-PGJ(2) by determining its anticancer effects in wild-type and doxorubicin-resistant ovarian carcinoma cells. Despite high expression of resistance-inducing genes like MDR1, Bcl2 and Bcl-xl, 15d-PGJ(2) strongly induced apoptosis in doxorubicin-resistant (A2780/AD) cells similar to the wild-type (A2780). This was found to be related to caspase-3/7- and NF-κB pathways but not to its PPARγ agonistic activity. 15d-PGJ(2) 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-PGJ(2) on cell migration and transformation using a wound-healing assay and morphological analyses, respectively. We found that 15d-PGJ(2) inhibited migration most likely due to NF-κB inhibition and induced transformation of the round-shape A2780/AD cells into elongated epithelial cells due to HDAC1 inhibition. Using a 15d-PGJ(2) analog, we found the mechanism of action of these new activities of 15d-PGJ(2) on SIRT1 and HDAC1 gene expressions and enzyme activities. In conclusion, the present study demonstrates that 15d-PGJ(2) 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.
authors.affiliation: Department of Pharmacokinetics, Toxicology and Targeting, Groningen Research Institute for Pharmacy, University of Groningen, Groningen, The Netherlands.
authors.forename: Edwin
authors.initials: E
authors.lastname: de Jong
authors.forename: Peter
authors.initials: P
authors.lastname: Winkel
authors.forename: Klaas
authors.initials: K
authors.lastname: Poelstra
authors.forename: Jai
authors.initials: J
authors.lastname: Prakash
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000473:pathology*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014945:Wound Healing / Q000187:drug effects; D051020:bcl-X Protein / Q000235:genetics
chemical_list: C097240:15-deoxy-delta(12,14)-prostaglandin J2; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D051020:bcl-X Protein; D004317:Doxorubicin; D011451:Prostaglandin-Endoperoxide Synthases; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D006655:Histone Deacetylases; D015230:Prostaglandin D2