Bcl-w Promotes Gastric Cancer Cell Invasion by Inducing Matrix Metalloproteinase-2 Expression via Phosphoinositide 3-Kinase, Akt, and Sp1

Abstract

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. (Cancer Res 2006; 66(10): 4991-5)

ICAM-3 enhances the migratory and invasive potential of human non-small cell lung cancer cells by inducing MMP-2 and MMP-9 via Akt and CREB

“…As ICAM-3 activated Akt in our previous study (26), we postulated these proteins were involved in increased cell migration and invasion by ICAM-3. In our results, inhibition of Akt suppressed activity/expression of MMP and cell migration/ invasion, which agree with previous results of Bae et al, Weng et al and Yoeli-Lerner et al that PI3 kinase/Akt promotes cell migration and invasion through the induction of MMP proteins and modulation of MMP expression, and they also indicated that treatment of LY294002 suppressed cell migration and invasion (27,29,30). Du and Montminy reported that CREB is located at downstream of Akt, which induced phosphorylation of Ser-133 of CREB and then stimulated expression of the target gene via the activation of CREB (35).…”

“…2A and B). It was shown in several cancer types that various factors induced high expression MMP-2 and MMP-9; Ionizing radiation promote hepatocellular carcinoma cell invasion with increase of MMP-9 expression (4), enhancement of Bcl-2 expression increase gastric cancer cell invasion with increase of MMP-2 expression and activity (27), insulin-like growth factor-1 (IGF-1) induces invasion of distinct breast cancer cell lines (MDA-MB231, MDA-MB-435 and SUM-159-PT) with induction of MMP proteins (30), and hepatitis B viral HBx protein increase hepatocellular carcinoma invasion potential with induction of MMP-9 gene expression (31). Our results also defined the role of ICAM-3 as an inducer of MMP proteins, and it increased cell migration and invasion via increase of activities of MMP-2 and -9.…”

“…Migration and invasion assays were performed as described by Bae et al (27). Collagen (3 μg/μl, Sigma)-coated transwells (0.8 μm pore; Corning, NY, USA) were used to detect cell migration and Matrigelcoated transwells (1 mg/ml, Invitrogen) were used to detect cell invasion.…”

.ALPHA.-Chaconine Inhibits Angiogenesis in Vitro by Reducing Matrix Metalloproteinase-2

“…Numerous reports have demonstrated that MMP-2 expression is critically mediated by MAPK members 13,15) and PI3K/Akt pathway. 23,33,34) MAPK and PI3K/Akt pathways also play an important role in endothelial cell viability, migration, and tube formation by specific stimuli. [13][14][15]25,35,36) Therefore, we examined the effect of a-chaconine on the activities of MAPK and PI3K/Akt signaling pathways.…”

Overexpression of Sp1 leads to p53‐dependent apoptosis in cancer cells

“…19,20 Interestingly, it has been found that Sp1 can also induce the expression of many antiapoptotic genes (such as survivin, bcl-x, and bcl-w). 20,21 Moreover, several recent studies have indicated that the overexpression of Sp1 causes apoptotic cell death in nontransforming cells, but the downregulation of the overexpressed Sp1 protein in human fibrosarcoma cell lines inhibits tumor formation. 13,22 Therefore, the effect of Sp1 overexpression on apoptosis regulation in transforming cells remains controversial, and the detailed mechanism of this process remains unclear.…”