Differentiation-inducing factor-1 (DIF-1) inhibits STAT3 activity involved in gastric cancer cell proliferation via MEK-ERK-dependent pathway
Differentiation-inducing factor-1 (DIF-1) inhibits STAT3 activity involved in gastric cancer cell proliferation via MEK-ERK-dependent pathway
复制标题
DOI：
10.1038/sj.onc.1206109
复制
发表时间：
2003-01-30
期刊：
影响因子：
8
通讯作者：
Chiba, T
中科院分区：
文献类型：
--
作者：
Kanai, M;Konda, Y;Chiba, T
分化诱导因子-1（DIF-1）是从网骨藻中分离得到的一种氯化六苯酮。DIF-1在几种类型的哺乳动物肿瘤细胞中表现出抗肿瘤活性，但其潜在机制仍不清楚。另一方面，最近的研究表明，组成性激活的STAT 3作为一种癌基因，并可能成为抗肿瘤药物的靶点。在本研究中，我们研究了DIF-1对胃癌细胞系增殖的影响以及对信号转导途径的影响，主要集中在STAT蛋白上。DIF-1抑制胃癌细胞增殖。Western blot分析和电泳迁移率变动分析显示DIF-1以MEK-ERK依赖的方式抑制胃癌细胞系AGS和MKN 28中STAT 3的活性。此外，阻断STAT 3活性的异位表达的显性负性STAT 3或Janus激酶抑制剂，tyrphostin AG 490，抑制细胞生长的AGS细胞。这些结果表明，STAT 3活性在AGS细胞中的细胞生长中起着重要作用，并且提高了抑制STAT 3活性是DIF-1在这些细胞中的抗肿瘤作用的机制之一的可能性。
Differentiation-inducing factor-1 (DIF-1) is a chlorinated hexaphenone isolated from Dictyostelium. DIF-1 exhibits antitumor activity in several types of mammalian tumor cells, although the underlying mechanisms remain unknown. On the other hand, recent studies indicate that constitutively activated STAT3 acts as an oncogene and could be a target for antitumor drug. In the present study, we examined the effects of DIF-1 on proliferation of gastric cancer cell lines as well as on its signal transduction pathways, focusing mainly on STAT proteins. DIF-1 inhibited proliferation of gastric cancer cells. Western blot analysis and electrophoretic mobility shift assay showed that DIF-1 inhibited STAT3 activity in an MEK-ERK-dependent manner in gastric cancer cell lines, AGS and MKN28. Moreover, blockade of STAT3 activity by ectopic expression of dominant-negative STAT3 or the Janus kinase inhibitor, tyrphostin AG490, inhibited cell growth of AGS cells. These results suggest that STAT3 activity plays an important role for cell growth in AGS cells, and raises the possibility that inhibition of STAT3 activity is one of the mechanisms responsible for the antitumor effect of DIF-1 in these cells.