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Suppression of apoptosis following hormone-retractory prostate cancer.

抑制激素抵抗性前列腺癌后的细胞凋亡。

基本信息

批准号：
10671460
负责人：
TAKEUCHI Takumi
金额：
$ 2.11万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10671460/
关键词：
Prostate Apoptosis ICE 腎細胞癌

项目摘要

Renal cell cancer is a unique solid tumor which occasionally shows spontaneous regression even at an advanced stage, of which underlying mechanism is not well understood. To investigate a potential role of a pro-apoptotic molecule caspase-1 in the growth regulation of renal cell cancer, we created transfectants expressing exogenous caspase-1 from a murine renal cancer cell line Renca Overexpression of caspase-1 did not affect growth of Renca cells in vitro at their exponential phase, but induced apoptotic cell death at 50-75% confluence, while control bells underwent apoptosis only after reaching 100% confluence. When implanted to the flank of a syngeneic BALB/c mouse, caspase-1 overexpressing Renca cells did not effectively establish growth as a solid tumor, forming a measurable tumor in only 7 of 11 (41%) animals, while control cells formed a tumor in 6 of 6 (100%) animals. The growth of tumors from caspase-1 overexpressing cells markedly slowed down after reaching 5-10 mm in diameter, and histological examination of such tumors revealed numerous apoptotic cells positively stained by TUNEL assay. Interestingly, endogenous caspase-1 was not detected in the tumors from control cells, which re-expressed caspase-1 when re-cultured and exposed to a demethylation reagent 5-aza-2'-deoxycytidine. Furthermore, treatment of a human renal cancer dell line ACHN with 5-aza-2'-deoxycytidine also recovered caspase-1 expression, which was not detected before treatment. These data suggest that silencing of caspase-1 through DNA methylation may be involved in the oncogenesis of some renal cell cancers growing as a solid tumor.

肾细胞癌是一种独特的实体肿瘤，有时甚至在晚期也会自发消退，其潜在机制尚不清楚。为了研究促凋亡分子caspase-1在肾细胞癌生长调控中的潜在作用，我们从小鼠肾癌细胞系Renca中制备了表达外源性caspase-1的转染物。caspase-1的过表达不影响Renca细胞在体外指数期的生长，但在50-75%的合流下诱导凋亡细胞死亡，而对照钟只有在达到100%合流后才发生凋亡。当将caspase-1过表达的Renca细胞植入到同基因BALB/c小鼠的侧腹时，没有有效地形成实体瘤，11只动物中只有7只（41%）形成可测量的肿瘤，而6只动物中的6只（100%）对照细胞形成肿瘤。caspase-1过表达细胞在直径达到5 ~ 10 mm后，肿瘤生长明显减慢，组织学检查发现TUNEL染色阳性的凋亡细胞较多。有趣的是，来自对照细胞的肿瘤中未检测到内源性caspase-1，当再培养并暴露于去甲基化试剂5-aza-2'-脱氧胞苷时，对照细胞重新表达caspase-1。此外，用5-aza-2'-脱氧胞苷治疗人肾癌dell细胞系ACHN也恢复了治疗前未检测到的caspase-1表达。这些数据表明，通过DNA甲基化沉默caspase-1可能参与了某些肾细胞癌作为实体瘤生长的肿瘤发生过程。