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

1.膳食纤维的抗结直肠癌作用与其发酵产物丁酸有关。本研究探讨激活素A是否介导丁酸诱导的结肠癌细胞生长停滞和凋亡。丁酸盐诱导人结肠癌细胞株HT-29 G1期停滞和凋亡。丁酸盐还以时间和剂量依赖的方式激活激活素A基因。由于毛霉素A还能激活激活素A基因，因此丁酸的作用可能与抑制组蛋白乙酰基酶有关。丁酸盐对激活素A基因的刺激似乎是癌细胞所特有的，因为正常细胞株对丁酸盐没有反应。外源性激活素A对HT-29细胞的生长无明显影响。免疫沉淀结合Western blotting显示激活素A可诱导HT-29细胞中Smad2的磷酸化，但不能诱导Smad2/3/4复合体的形成。该细胞系既不表达Smad4基因，也不表达Smad4蛋白。因此，我们认为HT-29细胞对激活素A的无反应性是由于smad4.4基因突变所致。总之，丁酸上调的激活素A在结肠癌细胞中起旁分泌因子的作用，而不是自分泌因子。因此，激活素A并不介导丁酸诱导的结肠癌细胞生长停滞和凋亡。

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.