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Molecular targeted therapy by inducing cancer cell senesence

通过诱导癌细胞衰老的分子靶向治疗

基本信息

批准号：
14104014
负责人：
WAKE Norio
金额：
$ 72.47万
依托单位：
KYUSHU UNIVERCITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (S)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2006
项目状态：
已结题

项目摘要

A. We have cloned the NECCl gene from human chromosome 4 as a senescence inducing gene in choriocaracinoma cells. We investigated the placental anatomy of NECCl KO (-/-) mouse embryos. In the KO placeuta hypertrophy of giant cell layer and suppression of spongio-trophoblast layer formation were noticeable, respectively. NECCl expression was transiently detected in 8.5-11.5 dpc wild type mouse placenta. NECCl was involved in the negative regulation of differentiation from trophoblast stem cell to giant cell.B. We have cloned the EGLNl gene that has the potential to induce endometrial cancer cell senescence from lg42 region. EGLNl was a member of prolyl hydroxylase family and regulated HIF1 α protein degradation. Inhibition of HIFl α-mediated signaling by FIH or HIFlsiRNA also induced the cancer cell senescence. Overexpression of EGLNl in endometrial cancer cells was able to induce cell senescence through upregulation of p21 CDK ihibitor.C. We found the ER α activation by the oncogenic K-Ras mutant. Expression of PR or dominant-negative ER mutant elicited the cancer cell senescence. ER α inactivation resulted in the downregulation of MDM2 followed by p53 activation and subsequent p21 upregulation. We have demonstrated the efficacy of new therapies targetted i)functional inactivation of ER α and ii)suppression of MDM2 protein expression, respectively.D. We have demonstrated the anti-tumor activity of Sodium Butyrate and Valproic acid that are HDAC inhibitors. Both agents were able to induce cancer cell senescence through p21 upregulation. This effect was independent of p53. Now we are planning the clinical research by using Valproic acid.

A.我们从人4号染色体上克隆了NECCl基因作为绒毛膜癌细胞中的衰老诱导基因。我们研究了NECCl KO（-/-）小鼠胚胎的胎盘解剖。在KO胎盘巨细胞层肥大和海绵滋养层形成的抑制是明显的，分别。在8.5- 11.5dpc野生型小鼠胎盘中瞬时检测到NECCl表达。NECCl参与了滋养层干细胞向巨细胞分化的负向调节。我们从lg 42区域克隆了具有诱导子宫内膜癌细胞衰老潜力的EGLN 1基因。EGLN 1是脯氨酰羟化酶家族的成员，调节HIF 1 α蛋白的降解。通过FIH或HIFl siRNA抑制HIFl α介导的信号传导也诱导癌细胞衰老。EGLN 1在子宫内膜癌细胞中的过表达能够通过上调p21 CDK抑制剂诱导细胞衰老。我们发现致癌K-Ras突变体可激活ER α。PR或显性负性ER突变体的表达引起癌细胞衰老。ER α失活导致MDM 2下调，随后是p53激活和随后的p21上调。我们已经证明了新疗法的有效性，分别靶向i）ER α的功能性失活和ii）MDM 2蛋白表达的抑制。我们已经证明了HDAC抑制剂丁酸钠和丙戊酸的抗肿瘤活性。这两种药物都能够通过p21上调诱导癌细胞衰老。这种作用与p53无关。目前，我们正在计划使用丙戊酸进行临床研究。

项目成果

期刊论文数量（17）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Genome-wide definitive haplotypes determined using a collection of complete hydatidiform moles

DOI：
10.1101/gr.4371105
发表时间：
2005-11-01
期刊：
GENOME RESEARCH
影响因子：
7
作者：
Kukita, Y;Miyatake, K;Hayashi, K
通讯作者：
Hayashi, K

Genetic origin and imprinting in hydatidiform moles. Comparison between DNA polymorphism analysis and immunoreactivity of p57KIP2.

葡萄胎的遗传起源和印记。

DOI：
发表时间：
2005
期刊：
Journal of reproductive Medicine 50(5)
影响因子：
0
作者：
Taki M;Kyo S et al.;峯克也;峯克也;Kato H;竹下俊行;Horiuchi;峯克也;Kamikihara T;Arima T;Kihara M
通讯作者：
Kihara M

Expression of progesterone receptor B is associated with G0/G1 arrest of the cell cycle and growth inhibition in NIH3T3 cells.

孕激素受体 B 的表达与 NIH3T3 细胞中细胞周期的 G0/G1 停滞和生长抑制相关。

DOI：
发表时间：
2005
期刊：
Exp Cell Res. 305(2)
影响因子：
0
作者：
Kamikihara;T.;Arima;T.;Kato;K.;Matsuda;T.;Kato;H.;Douchi;T.;Nagata;Y.;Wake;N;Horiuchi S
通讯作者：
Horiuchi S

Zhou Y et al.: "Identification of FOXC1 as a TGF-β1 responsive gene and its involvement in negative regulation of cell growth"Genomics. 80,5. 465-472 (2002)

Zhou Y等人：“FOXC1作为TGF-β1响应基因的鉴定及其参与细胞生长的负调节”Genomics 80,5 (2002)。