Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.24.35 (matrix metalloproteinase 9)
 2,207 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Increased mortality of patients with oral cancer largely reflects the local and regional spread of the disease. The invasiveness of these tumours requires hydrolases which are regulated through AP-1-dependent transcriptional mechanisms. Since the amount/activity of transcription factors bound to the AP-1 motif are regulated partly through the extracellular signal-regulated kinases (ERK1/ERK2), we determined the effect of PD 098059, an inhibitor of ERK1/ERK2 activation, on the in vivo invasiveness of a human squamous cell carcinoma cell line (UM-SCC-1) derived from the oral cavity. We utilized the floor of mouth musculature consisting of the mylohyoid, geniohyoid and genioglossus muscle (which are sequentially arranged), as a natural barrier to assess tumour spread in vivo in the nude mouse. Mice were inoculated with tumour cells superficial to the mylohyoid muscle. After 18 days, tumours were injected with either empty liposomes (control) or liposomes containing 5 microM PD 098059 and, after an additional 22 days, the jaws of mice examined histologically. Highly infiltrative tumours, which had penetrated the genioglossus muscle, were evident in 10/12 control mice. In contrast, in 9/12 mice in which the tumours were injected with PD 098059, tumours did not extend beyond the mylohyoid or geniohyoid muscles. Tumours penetrated bone nutrient canals in 7/12 control mice but in only 3/12 PD 098059-treated mice. Neurotropism, characteristic of aggressive oral squamous cell carcinoma, was evident in 6/12 control mice but was completely abolished (0/12 mice) in the PD 098059-treated mice. Using a staging system based on the muscle layer involved, neurotropism, as well as bone involvement, we found the inhibition of invasion to be statistically significant (P < 0.01). The reduced invasiveness of the PD 098059-liposome-treated oral cancers was associated with diminished 92-kDa type IV collagenase and ERK1/ERK2 activities but was not a consequence of a slower tumour growth rate. This is the first study to demonstrate reduced in vivo invasiveness of a malignancy brought about by an inhibitor of ERK1/ERK2 activation. These results raise the exciting possibility that second generation PD 098059 congeners may reduce the spread of the disease in patients afflicted with oral cancers.
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PMID:PD 098059, an inhibitor of ERK1 activation, attenuates the in vivo invasiveness of head and neck squamous cell carcinoma. 1042 44

Collagenase-3 (MMP-13) is a human matrix metalloproteinase specifically expressed by transformed squamous epithelial cells, i.e. squamous cell carcinoma (SCC) cells in culture and in vivo. Here, we have elucidated the signaling pathways regulating MMP-13 expression in transformed human epidermal keratinocytes, i.e. ras-transformed HaCaT cell line A-5 and cutaneous SCC cell line (UT-SCC-7). Treatment with tumor necrosis factor-(alpha) (TNF-(alpha) resulted in activation of extracellular signal-regulated kinase (ERK)1,2, Jun N-terminal kinase and p38 mitogen-activated protein kinase (MAPK) in both cell lines. In addition, transforming growth factor-(beta) (TGF-(beta) activated p38 MAPK in both cell lines, and ERK2 in A-5 cells. Selective inhibition of p38 activity with SB 203580 abolished the enhancement of MMP-13, as well as collagenase-1 (MMP-1) and 92-kDa gelatinase (MMP-9) expression by TNF-(alpha) and TGF-(beta). Blocking the ERK1, 2 pathway by PD 98059 had no effect on the induction of MMP-13 expression by TNF-(alpha) or TGF-(beta), but potently suppressed MMP-1 and MMP-9 production. Inhibition of p38 activity by SB 203580 also suppressed collagenolytic activity produced by both cell lines and inhibited invasion of TNF-(alpha) or TGF-(beta) stimulated A-5 cells through type I collagen and reconstituted basement membrane (Matrigel). These results show that activation of p38 MAPK pathway plays a crucial role in the invasive phenotype of transformed squamous epithelial cells, suggesting p38 MAPK as a target to specifically inhibit their invasion.
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PMID:Expression of collagenase-3 (MMP-13) and collagenase-1 (MMP-1) by transformed keratinocytes is dependent on the activity of p38 mitogen-activated protein kinase. 1063 74

Heregulin (HRG) and type I receptor tyrosine kinase (RTK) expression was investigated in the highly invasive and metastatic LM3 cell line, our previously described model of metastasis for mammary cancer (Bal de Kier Joffe et al. [1986] Invasion Metastasis 6:302-12; Urtreger et al. [1997] Int J Oncol 11:489-96). Although LM3 cells do not express HRG, they exhibit high levels of ErbB-2 and ErbB-3 as well as moderate expression of ErbB-4. Addition of exogenous HRGbeta1 resulted in inhibition of both proliferation and migration of LM3 cells. HRGbeta1 was also able to decrease the activity of urokinase-type plasminogen activator (uPA) and matrix metalloproteinase 9 (MMP-9), 2 key enzymes in the invasion and metastatic cascade. HRGbeta1 treatment of LM3 cells induced tyrosine phosphorylation of ErbB-2, ErbB-3 and ErbB-4 as well as the formation of ErbB-2/ErbB-3 and ErbB-2/ErbB-4 heterodimers. Assessment of the signaling pathways involved in HRGbeta1 action indicated that the addition of HRGbeta1 to LM3 cells resulted in activation of phosphatidylinositol 3- kinase (PI-3K) and in strong induction of the association of the p85 subunit of PI-3K with ErbB-3. HRGbeta1 also caused the rapid activation of ERK1/ERK2 and Stat3 and Stat5 (signal transducers and activators of transcription [STAT]). This is the first demonstration of the ability of HRGbeta1 to activate STATs in mammary tumor cells. Blockage of PI-3K activity with its chemical inhibitor wortmannin, or of MEK1/ERKs activity with PD98059, resulted in suppression of the ability of HRGbeta1 to inhibit LM3 cell growth. Notwithstanding the suppression of these 2 signaling pathways, HRGbeta1 still proved capable of inhibiting uPA activity. Therefore, our results provide evidence that signaling pathways involved in HRGbeta1-induced proliferation appear to be distinct from those involved in HRGbeta1 regulation of uPA, a protease that plays a pivotal role in invasion and metastasis.
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PMID:Heregulin inhibits proliferation via ERKs and phosphatidyl-inositol 3-kinase activation but regulates urokinase plasminogen activator independently of these pathways in metastatic mammary tumor cells. 1220 1

The epidermal growth factor (EGF) and transforming growth factor beta (TGFbeta) families of signaling molecules play a major role in growth and development of embryos. Abrogation of either signaling pathway results in defects in embryogenesis, including cleft palate. In the developing palate, both EGF and TGFbeta regulate cellular proliferation, extracellular matrix synthesis, and cellular differentiation but often in an opposing manner. Evidence from various adult cell types suggests the existence of cross talk between the EGF and TGFbeta signaling pathways, although it is unclear whether such cross talk exists in murine embryonic maxillary mesenchymal cells, from which the developing palate is derived. In this study, embryonic maxillary mesenchymal cells in culture were treated with EGF and TGFbeta, either singly or in combination, and the cells were subsequently examined for signaling interactions between these two pathways. Immunoblot analyses of nuclear extracts of embryonic maxillary mesenchymal cells revealed that TGFbeta-induced nuclear translocation of Smad 2 and Smad 3 proteins was not affected by EGF. Conversely, immunoblot analyses of whole-cell extracts of these cells indicated that EGF-induced phosphorylation of extracellular signal-regulated kinase proteins, ERK1 and ERK2, was not affected by TGFbeta. Expression of a transfected luciferase reporter gene driven by a promoter with Smad binding elements was induced by TGFbeta in these cells but was not affected by EGF. Last, TGFbeta was found to induce expression of the endogenous gelatinase B gene in embryonic maxillary mesenchymal cells; however, this effect was independent of any interaction of EGF. Collectively, data from this study suggest that the EGF and TGFbeta signal transduction pathways do not converge in murine embryonic maxillary mesenchymal cells.
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PMID:Divergence of epidermal growth factor - transforming growth factor beta signaling in embryonic orofacial tissue. 1288 Mar 67

The ability of cancer cells to proliferate abnormally and invade surrounding tissue is among the most important features of the malignant phenotype. The mechanisms by which the mitogen activated protein kinase (MAPK) cascade regulates these phenotypes have been investigated for many years. Activated GTP bound Ras binds the upstream protein kinases Raf-1 and B-Raf. The MAPK kinases 1 and 2, known as MKK or MEK, are phosphorylated and activated by Raf. MEKs phosphorylate the extracellular signal regulated kinases ERK1 and ERK2. A unique member of the MAPK family is p97MAPK, the human homolog of rat ERK3. p97MAPK is ubiquitously expressed but whether its cellular functions are different from ERK1 and ERK2 is unknown. p97MAPK is highly expressed in human cancer cell lines. In the present study, expression of p97MAPK was unique among the ERK family in that its expression was induced when human carcinoma cell lines are plated on type IV collagen. This increased expression correlated with slower cancer cell proliferation on collagen compared to plastic tissue culture dishes. Overexpression of p97MAPK was sufficient to inhibit cellular proliferation with concomitant changes in cell cycle regulatory protein expression. p97MAPK also inhibited cancer cell migration and invasion by decreasing Rac1 expression but not that of matrix metalloproteinase 9 which is regulated by other ERKs. These data represent the first reported function of p97MAPK in human cancer cells.
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PMID:Induction of p97MAPK expression regulates collagen mediated inhibition of proliferation and migration in human squamous cell carcinoma lines. 1506 37

Reactive oxygen species (ROS) and the coupled oxidative stress have been associated with tumor formation. Several studies suggested that ROS can act as secondary messengers and control various signaling cascades. In the present studies, we characterized the oxidative stress status in three different prostate cancer cells (PC3, DU145, and LNCaP) exhibiting various degree of aggressiveness and normal prostate cells in culture (WPMY1, RWPE1, and primary cultures of normal epithelial cells). We observed increased ROS generation in cancer cells compared with normal cells, and that extramitochondrial source of ROS generator, NAD(P)H oxidase (Nox) systems, are associated with the ROS generation and are critical for the malignant phenotype of prostate cancer cells. Moreover, diphenyliodonium, a specific Nox inhibitor, blocked proliferation, modulated the activity of growth signaling cascades extracellular signal-regulated kinase (ERK)1/ERK2 and p38 mitogen-activated protein kinase as well as AKT protein kinase B, and caused cyclin B-dependent G(2)-M cell cycle arrest. We also observed higher degrees of ROS generation in the PC3 cells than DU145 and LNCaP, and that ROS generation is critical for migratory/invasiveness phenotypes. Furthermore, blocking of the ROS production rather than ROS neutralization resulted in decreased matrix metalloproteinase 9 activity as well as loss of mitochondrial potential, plausible reasons for decreased cell invasion and increased cell death. Taken together, these studies show, for the first time, the essential role of ROS production by extramitochondrial source in prostate cancer and suggest that therapies aimed at reducing ROS production might offer effective means of combating prostate cancer in particular, and perhaps other malignancies in general.
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PMID:Oxidative stress is inherent in prostate cancer cells and is required for aggressive phenotype. 1833 58