Abstract
15-deoxy-delta-12,14-prostaglandin-J2 (15d-PGJ2), 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-PGJ2 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-PGJ2 strongly induced apoptosis in doxorubicin-resistant (A2780/AD) cells similar to the wild-type (A2780). This was found to be related to caspase-3/7- and NF-κB pathways but not to its PPARγ 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-κB 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.
Highlights
Prostaglandins (PGs) are a family of biologically active endogenous metabolites of arachidonic acid
Since the transformation of cells might be related to epithelialmesenchymal transition (EMT) process, we examined the expression of snail and e-cadherin transcripts and found that the ratio of snail to e-cadherin was increased in both cell types after the exposure of 2.5 mM 15d-PGJ2 though the differences were not statistically significant
We have demonstrated the effects of 15dPGJ2, a product of cyclo-oxygenase activity and as an endogenous peroxisome proliferator2activated receptor gamma (PPARc) agonist, on apoptosis, drug resistance, cell migration and transformation of cancer cells
Summary
Prostaglandins (PGs) are a family of biologically active endogenous metabolites of arachidonic acid. Knowing the involvement of NF-kB pathway in the regulation of multidrug resistance (MDR1) and anti-apoptotic genes (Bcl-2 and Bcl-xl) [9], we aimed to investigate whether 15d-PGJ2 is capable of inducing apoptosis in doxorubicin-resistant cancer cells compared to the wild-type. We compared the SIRT1 expression in human wild-type and doxorubicin resistant ovarian cancer cells and examined the effects of 15d-PGJ2 on this SIRT1 gene expression. During these experiments, we noticed that 15d-PGJ22treated doxorubicinresistant cells transformed from round-shaped cells to an elongated type. We noticed that 15d-PGJ22treated doxorubicinresistant cells transformed from round-shaped cells to an elongated type We further investigated this phenotypic change and found that 15d-PGJ2 induced these effects by inhibiting class-I HDAC enzymes. Our results show many new activities of this endogenous arachidonic acid metabolite on cancer cells and illuminate the mechanism of action of this cyclo-oxygenase product
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