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Molecular analysis and application of differentiation induction therapy with intra-nuclear receptor and intra-cellular signal transduction factor

核内受体和细胞内信号转导因子分化诱导治疗的分子分析及应用

基本信息

批准号：
12470259
负责人：
SHIMADA Yutaka
金额：
$ 6.59万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12470259/
关键词：
Intra-nuclear receptor PPARgamma RXR Intra-cellular signal transduction factor EGF STAT INFgamma 分化誘導療法

项目摘要

Interferon gamma as well as EGF inhibited the growth of esophageal cancer cells in 50% of the cell lines.STAT1 dominant negative cells demonstrated that this inhibitory effect was dependent on the STAT1. STATsignaling pathway was not harmful and induced Involculin in the normal esophageal squamous cell (NESC). In the KYSE70 cell which was not inhibited by EGF and INF gamma, hospholylation of the EGFR was not observed and the lack of INF gamma receptor was demonstrated. The growth of xeno-transplanted cells were inhibited by INF gamma and bioassay using explant culture was being checkedto predict INFgamma sensitivity.A specific ligand of PPARγ, troglitazone, led to G1 accumulation with the increase in p27 (Kip1), butnot p21 (Waf1/Cip1), and inhibited cellular proliferation in a pancreatic cancer cell line, Panc-1. The overexpression of PPARγ in a pancreatic cancer cell line, KMP-3, caused lipid accumulation, which suggested cell growth in some cancers might be inhibited, at least in par … More t, through terminal differentiation in the adipogenic lineage. In addition, implanted Panc-1 tumors in nude mice showed significant inhibition of tumor growth, when treated with pioglitazone, another specific ligand of PPARγ.RT-PCR andwestern blot analysis demonstrated that all ten tested human esophageal SCCcells, KYSE series, expressed PPAR gamma and RXR alfa. In luciferase assay, both troglitazone and pioglitazone transactivated the transcription of a peroxisome proliferator response element-driven promoter in a dose dependent fashion and when applied with 9-cis retinoic acid (9CRA), relative luciferase ctivity was elevated more strongly. Troglitazone inhibited growth of all ten tested cell lines where as pioglitazone inhibited 6 of these cell lines. In KYSE270 cells, cell cycle analysis by flow cytometry demonstrated that TZDs and 9CRA increased subG1 phase. Poly (ADP-ribose) polymerase (PARP) protein cleavage band was observed in the cells treated with TZDs and 9CRA. PARP cleavage band appeared at an early time point in the cells treated with both troglitazone and 9CRA, compared with pioglitazone and 9CRA simultaneously applied cells. P27 protein expression was increased to only the cells reated with both troglitazone and 9CRA. Simultaneous treatment of TZD and 9CRA is a promising therapeutic strategy of human esophageal squamous cell carcinoma. Less

干扰素γ和EGF对50%的食管癌细胞株的生长有抑制作用，STAT 1显性阴性细胞显示这种抑制作用依赖于STAT 1。STAT信号通路在正常食管鳞状细胞（NESC）中无损伤并诱导Involculin表达。在不受EGF和INF γ抑制的KYSE 70细胞中，未观察到EGFR的磷酸化，并且证明了INF γ受体的缺乏。IFN γ可抑制胰腺癌细胞株Panc-1的生长，并可通过体外培养的方法预测其对IFN γ的敏感性。在胰腺癌细胞株Panc-1中，PPARγ的特异性配体曲格列酮（troglitazone）可诱导G1期细胞聚集，并可抑制p27（Kip 1）的表达，但对p21（Waf 1/Cip 1）无影响。在胰腺癌细胞系KMP-3中，过表达的PPARγ导致脂质积累，这表明在某些癌症中细胞生长可能受到抑制，至少在正常情况下是如此。 ...更多信息 t，通过成脂谱系的终末分化。RT-PCR和western blot分析表明，10株KYSE系人食管鳞癌细胞均表达PPAR γ和RXR α。在荧光素酶试验中，曲格列酮和吡格列酮均以剂量依赖性方式反式激活过氧化物酶体增殖反应元件驱动的启动子的转录，并且当与9-顺式视黄酸（9 CRA）一起应用时，相对荧光素酶活性更强烈地升高。曲格列酮抑制了所有10种测试细胞系的生长，而吡格列酮抑制了其中6种细胞系。流式细胞仪检测KYSE 270细胞周期发现TZDs和9 CRA使细胞亚G1期增加。TZDs和9 CRA处理的细胞中观察到聚ADP核糖聚合酶（PARP）蛋白裂解带。与吡格列酮和9 CRA同时应用的细胞相比，曲格列酮和9 CRA处理的细胞在较早的时间点出现PARP裂解带。P27蛋白表达仅在曲格列酮和9 CRA处理的细胞中增加。TZD联合9 CRA治疗食管鳞癌是一种有前景的治疗策略。少