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

Abstract

Abstract.We have previously reported that intercellular adhesion molecule-3 (ICAM-3) is associated with an increase of cellular radio-resistance and cancer cell proliferation. In this study, we hypothesized that ICAM-3 has an additional effect on cancer cell migration and invasion because molecules induced by ICAM-3 are known as regulators of cell migration and invasion. To examine this hypothesis, we used NCI-H1299 non-small cell lung cancer (NSCLC) cell line (p53 and PTEN null cell) and constructed an ICAM-3-over-expressing stable transfectant, which exhibited increased cell migration and invasion. The increased migration and invasion resulted from up-regulation of expression and activities of MMP-2 and MMP-9. ICAM-3 also increased Akt phosphorylation, which caused an increase in cellular migration/invasion and MMP activities. Activity of several transcriptional factors located downstream in the Akt pathway was also tested, and constitutive activation of adenosine 3', 5'-monophosphate response element-binding protein (CREB) by ICAM-3 was detected. Blockage of the Akt pathway attenuated CREB activation, and a decrease in CREB expression reduced cellular migration/invasion and activity of MMPs. This result indicates that CREB functions in the signaling pathway between Akt and MMP. We also showed ICAM-3-induced cell migration and invasion in NCI-H460 NSCLC cells (wild-type p53 and PTEN cell) through the same signaling pathway. Taken together, our findings suggest that ICAM-3 stimulates cancer cell migration/ invasion via ICAM-3/Akt/CREB/MMP pathway regardless of p53 and PTEN status, and this reflects the possibility that ICAM-3 could be considered as a candidate for anti-cancer drug development and as a cancer diagnostic marker.

Colorectal Carcinogenesis: Connecting K-RAS–Induced Transformation and CREB Activity In Vitro and In Vivo

“…Although the binding of CREB to the MMP-2 and MMP-9 promoter had already been shown in different studies (43,44), this effect has not yet been linked to RAS transformation. These data are in line with reports demonstrating that CREB protein elimination decreased the activities of MMP in NSCLC (45) and melanoma (42).…”

Brain-Derived Neurotrophic Factor Induces Matrix Metalloproteinase 9 Expression in Neurons via the Serum Response Factor/c-Fos Pathway

“…In contrast with previous reports showing regulation of MMP-9 expression by CREB and its cofactors in nonneuronal cells (47,48), our data indicate that in neurons BDNF-induced MMP-9 transcription is not mediated by CREB activity. However, as already mentioned, MMP-9 gene expression seems to be modulated in a cell type/stimulus-specific manner.…”

“…As in nonneuronal cells, MMP-9 transcription has been shown to be regulated by another transcription factor, the cAMP response element binding protein (CREB) and its coactivators CREB binding protein (CBP) and p300 (47,48); we verified whether CREB contributes to BDNF-mediated MMP-9 transcription in neurons. We used two different approaches to inhibit endogenous CREB in neurons: we overexpressed inducible cyclic AMP early repressor 2␥ (ICER II␥) (35), which is an endogenous repressor of CREB, or a mutant form of CREB (A-CREB) that inhibits DNA binding of endogenous CREB (34).…”

cAMP-response Element-binding Protein (CREB) and NF-κB Transcription Factors Are Activated during Prolonged Hypoxia and Cooperatively Regulate the Induction of Matrix Metalloproteinase MMP1

“…NF-B is reported to also induce several MMPs upon cytokine activation, including MMP9, MMP13, and MT1-MMP (10,32,33). Similarly, CREB induces MMP2, MMP9, and MMP13 (34,35). Therefore, synchronized activation of CREB and NF-B during prolonged hypoxia might control the timing of metastasis, which is mediated by the orchestration of MMP1 and other MMPs (9).…”