Anticancer Effects of 15d-Prostaglandin-J2 in Wild-Type and Doxorubicin-Resistant Ovarian Cancer Cells: Novel Actions on SIRT1 and HDAC
Anticancer Effects of 15d-Prostaglandin-J2 in Wild-Type and Doxorubicin-Resistant Ovarian Cancer Cells: Novel Actions on SIRT1 and HDAC
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DOI：
10.1371/journal.pone.0025192
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发表时间：
2011-09-21
期刊：
影响因子：
3.7
通讯作者：
Prakash, Jai
中科院分区：
文献类型：
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作者：
de Jong, Edwin;Winkel, Peter;Prakash, Jai
15-deoxy-delta-12，14-prophylandin-J（2）（15 d-PGJ（2））是一种花生四烯酸代谢物和天然的过氧化物酶体增殖体激活受体γ激动剂，已知可诱导肿瘤细胞凋亡。在这项研究中，我们通过测定15 d-PGJ（2）在野生型和多柔比星耐药卵巢癌细胞中的抗癌作用来研究其新的治疗潜力。尽管耐药诱导基因如MDR 1、Bcl 2和Bcl-xl的高表达，但15 d-PGJ（2）在阿霉素耐药（A2780/AD）细胞中与野生型（A2780）类似地强烈诱导凋亡。发现这与半胱天冬酶-3/7-和NF-κ B途径有关，但与其PPAR γ激动活性无关。15 d-PGJ（2）还能够在低剂量下降低A2780/AD细胞的阿霉素耐药性，如通过抑制MDR 1（p-糖蛋白）和SIRT 1（药物衰老基因）的基因表达所证实的。我们还分别使用伤口愈合试验和形态学分析研究了15 d-PGJ（2）对细胞迁移和转化的影响。我们发现，15 d-PGJ（2）抑制迁移最可能是由于NF-κ B抑制和诱导的圆形A2780/AD细胞转化为细长的上皮细胞由于HDAC 1抑制。使用15 d-PGJ（2）类似物，我们发现了15 d-PGJ（2）的这些新活性对SIRT 1和HDAC 1基因表达和酶活性的作用机制。总之，本研究表明15 d-PGJ（2）具有杀死耐药肿瘤细胞的高治疗潜力，并且这种环加氧酶产物对SIRT 1和HDAC的新描述的抑制作用将为癌症治疗提供新的机会。
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.