Bcl-2 Promotes Invasion and Lung Metastasis by Inducing Matrix Metalloproteinase-2

Abstract

Bcl-2 is involved in the progression of human malignancies, but the precise role and mechanism of Bcl-2 for tumor invasion and metastasis remains unclear. In this study, we have investigated the role and mechanism of Bcl-2 on tumor cell invasion and metastasis by using Bcl-2 overexpressing non-small cell lung cancer cells. Matrix metalloproteinases (MMPs) are important proteins involved in the processes of tumor invasion and metastasis. In vitro Matrigel invasion assays showed that Bcl-2 overexpression increased tumor cell invasion by 15-fold. Moreover, Bcl-2 overexpression enhanced in vivo lung metastasis by 4-fold. Consistent with its effect on invasion and metastasis, Bcl-2 overexpression induced not only MMP-2 mRNA and its protein expression, but this also activated the pro-MMP-2 protein to its active form. To explore the induction mechanism of MMP-2 by Bcl-2, we investigated the effects of Bcl-2 overexpression on MMP-2 transcriptional regulation. Nuclear run-on assays showed a 6-fold increase in the transcription rate of MMP-2 mRNA in the Bcl-2 transfectants (H157/Bcl-2) compared with that of the H157/vector control cells (H157/C). Overexpression of Bcl-2 induced the nuclear transcription factor activator protein 1 family, including the c-Jun, JunD, c-Fos, FosB, and Fra-1 proteins. Reporter assays combined with deletion mutagenesis analysis and gel shift assays showed the involvement of activator protein 1 in the activation of MMP-2 promoter activity by Bcl-2. Taken together, we have shown that Bcl-2 promotes tumor invasion and lung metastasis by inducing MMP-2 gene expression through the combined action of transcriptional and posttranslational mechanisms. (Cancer Res 2005; 65(13): 5554-60)

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

“…Nevertheless, Bcl-2 was found to be cytoprotective in gastric cancer cells, which suggests that the prosurvival activities of Bcl-2 family members do not always guarantee their invasion-promoting activities. Given that Bcl-2 overexpression can increase the invasive potential of other tumors, such as glioma (17) and nonsmall-cell lung cancer cells (18), the ability of Bcl-2 family members to support cell invasion seems to depend on tissue type.…”

Matrix Metalloproteinase-2 Protein in Lung Periphery Is Related to COPD Progression

“…48,49 While it is true that the presence of lung cancer in some of our patients may have influenced the results, we tried to avoid this bias by collecting lung tissue from areas not affected by tumor and by having included subjects with lung cancer in the control groups. Furthermore, since the highest MMP-2 expression was observed in the group without concomitant cancer (ie, smokers with severe COPD undergoing lung volume reduction surgery), we feel rather confident that our findings of an increased MMP-2 expression in COPD patients are valid.…”

NFV, an HIV-1 protease inhibitor, induces growth arrest, reduced Akt signalling, apoptosis and docetaxel sensitisation in NSCLC cell lines

“…The matrix metalloproteinases (MMPs) including MMP-2 degrade basement membranes and stromal extracellular matrix, resulting in tumour invasion and metastasis (Choi et al, 2005). NCI-H460 cells expressed MMP-2, and NFV downregulated this protein by 90% (Figure 2).…”