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Anticancer Effects of 15d-Prostaglandin-J(2) in Wild-Type and Doxorubicin-Resistant Ovarian Cancer Cells: Novel Actions on SIRT1 and HDAC

de Jong, E., Winkel, P., Poelstra, K. & Prakash, J., 21-Sep-2011, In : PLoS ONE. 6, 9, 10 p., 25192.

Research output: Contribution to journalArticleAcademicpeer-review

15-deoxy-delta-12,14-prostaglandin-J(2) (15d-PGJ(2)), an arachidonic metabolite and a natural PPAR gamma 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-kappa B pathways but not to its PPAR gamma 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-kappa B 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.

Original languageEnglish
Article number25192
Number of pages10
JournalPLoS ONE
Volume6
Issue number9
Publication statusPublished - 21-Sep-2011

    Keywords

  • 15-DEOXY-DELTA(12,14)-PROSTAGLANDIN J(2), INDUCE APOPTOSIS, IN-VIVO, TRANSCRIPTION, DEACETYLASE, CHEMOTHERAPY, EXPRESSION, SURVIVAL, SNAIL

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