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

Overexpression of p185(c-erbB2) (p185/NEU/HER2) by tumor cells is associated with a poor prognosis in many but not all studies of breast and ovarian cancer. The poor prognosis associated with overexpression of p185(c-erbB2) could result from an increased growth rate or increased invasive potential. The p185(c-erbB2) tyrosine kinase receptor can be activated with agonistic antibodies directed against p185(c-erbB2) or with the ligand heregulin through a combinatorial interaction with erbB3 or erbB4. Consequently, we have asked whether heregulin or agonistic antibodies increase anchorage-independent growth or invasiveness of the SKBr3 breast cancer cell line, which overexpresses p185(c-erbB2). Incubation of SKBr3 breast cancer cells with heregulin inhibited anchorage-independent growth while enhancing tyrosine phosphorylation of p185(c-erbB2). Heregulin treatment also increased adhesion of SKBr3 cells to plastic and increased invasiveness of tumor cells into Matrigel membranes while increasing expression of the CD44 (HCAM) and CD54 (ICAM-1) adhesion molecules. Tumor cell invasion of Matrigel membranes was partially blocked by either anti-CD44 or anti-CD54 antibodies, indicating a role for these adhesion molecules in the invasion process. Compatible with the increased invasiveness, heregulin increased expression of the matrix metalloproteinase 9. In contrast, the agonistic anti-p185(c-erbB2) antibody ID5 induced only a subset of the responses induced by heregulin. ID5 induced tyrosine phosphorylation of p185(c-erbB2), increased invasiveness, and increased expression of CD44. Despite the similarity of effects of ID5 and heregulin on some outcomes, the ID5 antibody failed to increase adhesion to plastic, expression of CD54, or production of matrix metalloproteinase 9. Thus, the ID5 agonistic anti-p185(c-erbB2) antibody mimics rather than antagonizes some but not all of the actions of heregulin. Moreover, the poor prognosis of breast and ovarian cancers that overexpress p185(c-erbB2) could relate in part to enhanced invasiveness rather than to increased proliferative capacity.
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PMID:Heregulin and agonistic anti-p185(c-erbB2) antibodies inhibit proliferation but increase invasiveness of breast cancer cells that overexpress p185(c-erbB2): increased invasiveness may contribute to poor prognosis. 981 53

Evidence suggests that there is an association between the abnormal expression of members of the c-erbB receptor tyrosine kinase family and poor prognosis in head and neck squamous cell carcinomas (HNSCC). Until now, the relative contributions of different c-erbB ligands to HNSCC progression have not been clearly defined. In this paper we examined the effects of ligands with different c-erbB receptor specificities in terms of their stimulation of HNSCC proliferation, expression of matrix metalloproteinases (MMPs) and invasion. Heregulin-beta1 (HRG-beta1; selective c-erbB3/B4 ligand) was found to stimulate proliferation in the majority of cell lines, whereas epidermal growth factor (EGF; EGFR ligand) and betacellulin (BTC; EGFR/B4 ligand) induced variable responses. All three ligands up-regulated multiple MMPs including collagenases, stromelysins, matrilysin and gelatinase B (MMP-9) but had minimal or no effects on gelatinase A (MMP-2), MT1-MMP and tissue inhibitors of MMPs (TIMPs). MMP-9 mRNA was induced to a higher level than other MMPs, although with slower kinetics. HRG-beta1 was less active than EGF and BTC at the optimal concentration (relative potency of EGF:BTC:HRG = 3:4:1). In vitro invasion through Matrigel was also increased by all three ligands in proportion to their MMP up-regulation. A specific anti-EGFR monoclonal antibody (mAb ICR62) inhibited MMP up-regulation, migration and invasion induced by all three ligands, whereas an anti-c-erbB-2 mAb ICR12 inhibited mitogenic and motogenic responses following ligand stimulation but had no effect on MMP expression. These results suggest that c-erbB ligands may differentially potentiate the invasive phenotype of HNSCC via co-operative induction of cell proliferation, migration and proteolysis. The EGFR signalling pathway appears to be the dominant component controlling the proteolytic and invasive phenotype in HNSCC, whereas the c-erbB-2 signalling pathway is responsible, in part, for the mitogenic and motogenic effects of ligands.
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PMID:Differential modulation of proliferation, matrix metalloproteinase expression and invasion of human head and neck squamous carcinoma cells by c-erbB ligands. 1084 63

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

Curcumin has been shown to possess potent chemopreventive and antitumor effects on prostate cancer. However, the molecular mechanism involved in curcumin's ability to suppress prostate cancer cell invasion, tumor growth, and metastasis is not yet well understood. In this study, we have shown that curcumin can suppress epidermal growth factor (EGF)- stimulated and heregulin-stimulated PC-3 cell invasion, as well as androgen-induced LNCaP cell invasion. Curcumin treatment significantly resulted in reduced matrix metalloproteinase 9 activity and downregulation of cellular matriptase, a membrane-anchored serine protease with oncogenic roles in tumor formation and invasion. Our data further show that curcumin is able to inhibit the induction effects of androgens and EGF on matriptase activation, as well as to reduce the activated levels of matriptase after its overexpression, thus suggesting that curcumin may interrupt diverse signal pathways to block the protease. Furthermore, the reduction of activated matriptase in cells by curcumin was also partly due to curcumin's effect on promoting the shedding of matriptase into an extracellular environment, but not via altering matriptase gene expression. In addition, curcumin significantly suppressed the invasive ability of prostate cancer cells induced by matriptase overexpression. In xenograft model, curcumin not only inhibits prostate cancer tumor growth and metastasis but also downregulates matriptase activity in vivo. Overall, the data indicate that curcumin exhibits a suppressive effect on prostate cancer cell invasion, tumor growth, and metastasis, at least in part via downregulating matriptase function.
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PMID:Curcumin-targeting pericellular serine protease matriptase role in suppression of prostate cancer cell invasion, tumor growth, and metastasis. 2346 86