Bcl-w promotes gastric cancer cell invasion by inducing matrix metalloproteinase-2 expression via phosphoinositide 3-kinase, Akt, and Sp1
Bcl-w promotes gastric cancer cell invasion by inducing matrix metalloproteinase-2 expression via phosphoinositide 3-kinase, Akt, and Sp1
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DOI：
10.1158/0008-5472.can-05-4254
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发表时间：
2006-05-15
期刊：
影响因子：
11.2
通讯作者：
Um, Hong-Duck
中科院分区：
文献类型：
--
作者：
Bae, In Hwa;Park, Myung-Jin;Um, Hong-Duck
鉴于先前有报道称Bcl-w在胃癌细胞中表达，特别是在浸润性细胞中表达，我们研究了Bcl-w表达是否影响胃癌细胞的侵袭性。为了实现这一点，Bcl-w在贴壁型胃腺癌细胞系中过表达，发现这导致其迁移和侵袭潜力增加。当Bcl-2在相同的细胞类型中过表达时，这些影响不会被诱导。一致地，Bcl-w而不是Bcl-2的过表达增加了基质金属蛋白酶-2 （MMP-2）的表达，合成或天然的MMP-2抑制剂可消除Bcl-w诱导的细胞侵袭。Bcl-w过表达还激活了磷酸肌醇3-激酶（PI3K）、Akt和Sp1，并且使用药物抑制剂、显性阴性突变体或小干扰RNA阻断这些成分的作用，消除了Bcl-w诱导MMP-2和细胞侵袭的能力。PI3K/Akt信号的抑制也阻止了Sp1的激活。总的来说，我们的数据表明，Bcl-w，先前被证明可以增强胃癌细胞的生存能力，也可以通过PI3K、Akt和Sp1的顺序作用诱导MMP-2的表达，从而促进其侵袭性。
Given a previous report that Bcl-w is expressed in gastric cancer cells, particularly in those of an infiltrative morphology, we investigated whether Bcl-w expression influences the invasiveness of gastric cancer cells. To accomplish this, Bcl-w was overexpressed in adherent types of gastric adenocarcinoma cell lines, and this was found to result in an increase in their migratory and invasive potentials. These effects were not induced when Bcl-2 was overexpressed in the same cell types. Consistently, Bcl-w, but not Bcl-2, overexpression increased matrix metalloproteinase-2 (MMP-2) expression, and synthetic or natural inhibitors of MMP-2 abolished Bcl-w-induced cell invasion. Bcl-w overexpression also activated phosphoinositide 3-kinase (PI3K), Akt, and Sp1, and the blocking effects of each of these components using pharmacologic inhibitors, dominant-negative mutants, or small interfering RNA abolished the ability of Bcl-w to induce MMP-2 and cell invasion. The inhibition of PI3K/Akt signaling also prevented Sp1 activation. Overall, our data suggest that Bcl-w, which was previously shown to enhance gastric cancer cell survivability, also promotes their invasiveness by inducing MMP-2 expression via the sequential actions of PI3K, Akt, and Sp1.