摘要
背景：
过氧化物酶体增殖激活受体γ(PPARγ)是细胞核受体超家族的成员,最初发现它是脂肪细胞分化的重要调节因子,近期研究证明PPARγ也表达于不同类型的肿瘤细胞中参与调控肿瘤细胞的凋亡或分化。某些天然的和人工合成的配体结合于PPARγ,如天然配体15-脱氧-△12,14前列腺素J2(15d-PGJ2)和脂肪酸衍生物及合成类药物噻唑烷二酮类能激活PPARγ调控包括脂肪细胞分化和脂质存储等许多基因的表达。PPARγ激动剂在某些肿瘤中可诱导肿瘤细胞凋亡或分化而抑制恶性肿瘤发展,因此其在肿瘤学中有望成为防治肿瘤的因子之一。维甲酸类受体(RXR)属于类固醇/甲状腺激素受体超家族成员,是配体激活的转录因子,在多方面调节多细胞动物生命活动。这类受体包括大量天然和合成类视黄醇配体,其中9-顺式维甲酸(9-cisRA)是RXR的高效天然配体,可通过消除阻遏状态而激活RXR。PPARγ可与RXRα形成一个异源二聚体而激活下游基因的转录活性,引起一系列凋亡相关基因的表达,促进肿瘤细胞的凋亡或分化。
目的：
本文以人骨肉瘤细胞MG-63为靶细胞,研究PPARγ的内源性配体15-脱氧前列腺素2(15d-PGJ2)和维甲酸X受体(RXRα)的配体9-cisRA单独及联合作用对MG-63细胞增值活性的影响,探讨PPARy和RXRa配体诱导骨肉瘤细胞凋亡的作用机制,为抗肿瘤治疗寻找新的靶点。
方法：
1.采用噻唑蓝(MTT)比色法检测单独使用15d-PGJ2或9-cisRA以及两者联合作用对细胞增值的影响。2.FCM AnnexinV/PI双染色检测药物干预后对MG-63细胞的周期影响及细胞凋亡和坏死。3.逆转录聚合酶链式反应(RT-PCR)检测单独使用15d-PGJ2和9-cisRA以及两者联合作用对MG-63细胞中PPARy和RXRa mRNA的表达影响。4.通过免疫细胞化学技术检测药物干预后MG-63细胞中凋亡相关蛋白caspase3, p53, Bax/bcl-2的表达情况。
结果：
1.MTT结果显示：单独使用15d-PGJ2或9-cisRA均能够抑制细胞活性,各浓度剂量组与对照组比较有统计学意义(p<0.05),且随药物浓度增加作用增强。药物作用48h达到最佳抑制效果,48h、72h及96h无显著性差异(P>0.05)。联合用药对细胞的抑制作用明显高于单独用药组(p<0.05)；2.流式细胞术检测结果显示：加药组细胞G1期数量较对照组明显增多,S、G2/M期相应减少,且细胞凋亡率增高。联合用药组G1期细胞数及细胞凋亡率均明显高于单独用药组(p<0.05); 3.RT-PCR检测PPARy及RXRa mRNA的表达,并同时逆转录稳定的内参片段P-actin,以二者的面积灰度值比值作为该mRNA的相对表达量,PPARy mRNA的相对表达量分别为对照组0.94±0.23,5μM 9-cisRA组1.85±0.44,20μM 15d-PGJ2组2.06±0.35,联合组2.444±0.36；RXRamRNA的相对表达量分别是对照组1.06±0.16,5μM 9-cisRA组2.13±0.12,20μM 15d-PGJ2组1.78±0.31,联合组2.33±0.47,各加药组PPARy和RXRa mRNA的表达与对照组比较差异均有统计学意义(P<0.05)；且联合组目的基因表达均强于单独使用组(P<0.05)。4.免疫细胞化学结果显示：药物干预组凋亡相关蛋白caspase3和Bax表达与对照组比较显著增加,而p53和bcl-2表达下降(p<0.05),联合用药组的作用明显强于单独用药组(p<0.05)。
结论：
1.PPARy激动剂15d-PGJ2和RXRa配体9-cisRA及二者联合使用均可抑制人骨肉瘤MG-63细胞的生长,使细胞周期停滞在G1期且诱导细胞凋亡。联合用药强于单独用药,表明二者具有相加作用。
2.15d-PGJ2和9-cisRA可能通过增加PPARy及RXRa mRNA表达,上调凋亡相关蛋白Bax、caspase3及下调bcl-2、p53表达而诱导细胞凋亡。
3. PPARy及RXRa有望成为抗肿瘤药物治疗的新靶点。
Background:
Peroxisome proliferator activated receptor (PPARy) is the member of the nucleus receptor superfamily. PPARy is originally known as the important regulatory factor in adipocyte differentiation.Recent studies evidenced that PPARy was expressed in variety tumor cells and participate in the regulation of proliferation differentiation and apoptosis of tumor cells. Some natural or synthetic ligands such as 15-Deoxy-12,14-prostaglandin J2 (15d-PGJ2, the natural ligand) or fatty acid derivatives or thiazolidinediones (TZD) can activate PPAR gamma to regulate many downstream gene including adipocyte differentiation and lipid storage gene expression. PPAR gamma agonists,as the factor which restraining or preventing the development of malignancies,could inducing tumor cell apoptosis or differentiation.Accordingly PPAR gamma agonists may become a therapeutic method for phymatology in the future. Retinoic acid receptor (RXR) belongs to the steroid/thyroid hormone receptor superfamily, and the transcription factor can be activated by ligands to regulate various aspects of life in multicellular animals.This ligands is the most successful differentiation-inducing deagents in clinical now.The retinoic acid receptor has plenty of natural and synthetical retinol ligand, including natural ligand 9-cis retinoic acid is the most efficient ligands, which activate RXR by eliminating inhibition.In the beginning PPAR gamma is used to combine with RXR alpha in a heterologous dimer in order to activate downstream gene transcriptional activity,and then caused a series of apoptosis-related gene to expression, promote the tumor cell apoptosis or differentiation.
Purpose:
This paper used the human osteosarcoma cell line MG-63 as the target cell to investigate the influence of 15d-PGJ2 and 9-cisRA on the viability of MG-63 cell,and to explore the possibilities mechanism of PPAR gamma combined with RXR alpha to inhibit tumor growth. Expect to find out a new target in the treatment of tumor.
Methods:
1.Test the anti-proliferative effect in MG-63 cell treated with 15d-PGJ2 or 9-cisRA or both of them by MTT assay.2,MG-63 cell treated with 15d-PGJ2 or 9-cisRA or both of them was used to study the effects of cell cycle and apoptosis by flow cytometry.3,Detected the expression of PPARγand RXRαin the presence of 15d-PGJ2 or 9-cisRA or both by RT-PCR.4,Detected the expression of apoptosis-related gene caspase3,p53 and Bax/bcl-2 by immunocytochemistry to investigate the possibilities mechanism of PPAR gamma combined with RXR alpha induced cell apoptosis.
Results:
1,MTT assay showed that uesd 15d-PGJ2 or 9-cisRA separately took inhibitory effect on the growth of MG-63 in a dose-dependent manner,and each concentration of the drugs group had significant difference compared with the control group(p<0.05). After treated for 48h the drugs got the best inhibit effect. There were no significances compared the inhibit effect of 48h,72h and 96h(P>0.05). the combination group inhibitory effect was superior to those of 15d-PGJ2 or 9-cisRA(P<0.05).2, Flow cytometry showed that the proportion of G1 phase increased and the S phase decreased when treated with 15d-PGJ2 or 9-cisRA or 15d-PGJ2 combined with 9-cisRA,and associated with the increased apoptosis rate. The proportion of G1 and apoptosis rate of combination group was obviously higher than tthat in 15d-PGJ2 or 9-cisRA grou(P<0.05).3,RT-PCR used to detect the PPARy mRNA and RXRa Mrna,and reversely transcript the stable internal standard segementβ-actin at the same time, then the ratio of two area light degree (IA) was used as the relative expression of mRNA of the receptors.There is the amount of PPARy mRNA expression in each group:in control group is 0.94±0.23,in 5μM 9-cisRA group is 1.85±0.44,in 20μM 15d-PGJ2 group is 2.06±0.35,in combination group is 2.44±0.36; The amount of RXRa mRNA expression in each group:in control group is 1.06±0.16,in 5μM 9-cisRA group is 2.13±0.12,in 20μM 15d-PGJ2 group is 1.78±0.31,in combination group is 2.33±0.47. There were significant differences in eath drug group compared with control group(P<0.05);And the expressions in combination group were higher than 15d-PGJ2 group or 9-cisRA group(P<0.05).4, Immunocytochemistry demonstrated that compared with control group, in the drug intervention group the expression of caspase3 and Bax were increased.However the expression of p53 and bcl-2 was decreased(p<0.05).And the effect of the combination group were stronger than 15d-PGJ2 group or 9-cisRA group(P<0.05).
Conclusions:
1,15d-PGJ2(ligands of PPARy) and 9-cisRA(ligands of RXRa) were combined or used separately could inhibit the growth of MG-63 cell.And resulting in the restriction of MG-63 cell in its G0/G1 phase of the cell cycle and enhancing the apoptosis of MG-63 cell. The combination group were stronger than 15d-PGJ2 or 9-cisRA used separately.The results show that the two drugs have additive effect.
2,15d-PGJ2 and 9-cisRA induced the apoptosis of MG-63 cell may be realized by increased PPARy mRNA and RXRa mRNA level and then up-regulation of Bax and caspase3 expressions and down-regulation of bcl-2 and p53 expressions.
3,PPARy and RXRa may be a novel promising strategy for the treatment of malignant tumors.
引文
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