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Role of activin A in induction of growth arrest and apoptosis by butyrate in colon cancer cells

激活素 A 在丁酸盐诱导结肠癌细胞生长停滞和凋亡中的作用

基本信息

批准号：
13660114
负责人：
SONOYAMA Kei
金额：
$ 2.62万
依托单位：
Hokkaido University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13660114/
关键词：
Activin A Butyrate Colorectal cencer HT-29 Smad IEC-6 ビタミンD

项目摘要

1. Colorectal tumor-suppressing effect of dietary fiber has been reportedly associated with its fermentation product butyrate. The present study investigated whether activin A mediates butyrate-induced growth arrest and apoptosis in colon cancer cells.2. Butyrate induced G1 arrest and apoptosis in human colon cancer cell line HT-29. Butyrate also stimulated activin A gene in time-and dose-dependent manner. Because trichostain A also stimulated activin A gene, the effect of butyrate is possibly associated with the inhibition of histone acetylase. Stimulation of activin A gene by butyrate seems to be specific to cancer cells, as normal cell lines showed no response to butyrate.3. Exogenous activin A did not aggect the growth of HT-29 cells. Immuneprecipitation coupled with Western blotting revealed that activin A induced phosphorylation of smad2 but not complex formation of smad2/3/4 in HT-29 cells. The cell line expressed neither smad4 mRNA nor protein. It is thus suggested that unresponsiveness to activin A in HT-29 cells is due to mutation of smad4.4. Taken together, upregulated activin A by butyrate in colon cancer cells acts as paracrine factor rather than autocrine factor. Thus activin A does not mediate butyrate-induced growth arrest and apoptosis in colon cancer cells.

1. 据报道，膳食纤维对结直肠肿瘤的抑制作用与其发酵产物丁酸盐有关。本研究探讨激活素A是否介导丁酸盐诱导的结肠癌细胞生长阻滞和凋亡。丁酸盐诱导人结肠癌HT-29细胞G1阻滞和凋亡。丁酸盐对激活素A基因的刺激也呈时间和剂量依赖性。由于曲古霉素A也刺激了激活素A基因，丁酸盐的作用可能与抑制组蛋白乙酰化酶有关。丁酸盐对激活素A基因的刺激似乎是针对癌细胞的，因为正常细胞系对丁酸盐没有反应。外源性激活素A不影响HT-29细胞的生长。免疫沉淀结合Western blotting显示，激活素A诱导HT-29细胞smad2磷酸化，但不诱导smad2/3/4复合物的形成。该细胞系既不表达smad4 mRNA，也不表达smad4蛋白。因此，我们认为HT-29细胞对激活素A的无应答是由于smad4.4突变引起的。综上所述，丁酸盐在结肠癌细胞中上调激活素A作为旁分泌因子而非自分泌因子。因此激活素A不介导丁酸盐诱导的结肠癌细胞生长停滞和凋亡。