Mitogen-activated protein kinase (MAPK) regulates the expression of progelatinase B (MMP-9) in breast epithelial cells

Abstract

Mitogen‐activated protein kinases (MAPKs) play a major role in the mitogenic signal transduction pathway and are essential components of both growth and differentiation. Constitutive activation of the MAPK cascade is associated with the carcinogenesis and metastasis of human breast and renal cell carcinomas. The gelatinases B (MMP‐9) and A (MMP‐2) are 2 members of the matrix metalloproteinase (MMPs) family which are expressed in human cancers and thought to play a critical role in tumor cell invasion and metastasis. In a previous study, we have shown that EGF and amphiregulin upregulate MMP‐9 in metastatic SKBR‐3 cells but have no effect on MMP‐2 secretion. We now investigated specific step(s) in EGF‐induced signalling associated with regulation of cell proliferation and MMP‐9 induction. EGF‐induced signalling in SKBR‐3 cells was blocked by relatively specific inhibitors either on ras (FPT inhibitor‐I) or PI3 kinase (Wortmannin) or by reduction in EGF‐induced tyrosine kinase activity (RG 13022). Blocking these signalling pathways significantly inhibited of EGF‐induced cell proliferation but only partially reduced in EGF‐induced MMP‐9 secretion. In contrast, when SKBR‐3 cells were exposed to MEK inhibitor (PD 98059) or MAPK inhibitors (Apigenin or MAPK antisense phosphorothioate oligodeoxynucleotides), EGF‐induced cell proliferation, MMP‐9 induction and invasion through reconstituted basement membrane were significantly reduced. Our results suggest that interfering with MAPK activity may provide a novel means of controlling growth and invasiveness of tumors in which the signalling cascade is activated. Int. J. Cancer 82:268–273, 1999. © 1999 Wiley‐Liss, Inc.

Signaling pathways required for matrix metalloproteinase‐9 induction by betacellulin in head‐and‐neck squamous carcinoma cells

“…Although the present data and other reports 25,26,31,34,48 strongly suggest a role for MAPKs in MMP-9 regulation, involvement of PI3K in growth factor-induced MMP-9 production has not been extensively studied. Blocking of PI3K by selective inhibitors effectively inhibited BTC-enhanced MMP-9 expression in HNSCC cells, indicating that PI3K is required for this process.…”

“…Blocking of PI3K by selective inhibitors effectively inhibited BTC-enhanced MMP-9 expression in HNSCC cells, indicating that PI3K is required for this process. Reddy et al 48 reported that PI3K inhibition only partially blocked EGF induction of MMP-9 expression in mammary carcinoma cells, whereas both invasion and MMP-9 production were significantly dependent on MEK signaling. In contrast, roles for PI3K pathways in both basal and EGF-stimulated in vitro invasion and MMP-9 expression in ovarian cancer cells have been suggested, 27 as observed in our study.…”

Temporal and quantitative regulation of mitogen-activated protein kinase (MAPK) modulates cell motility and invasion

“…Previously published data shows that ERK1 and ERK2 are speci®cally activated by MEK1 because of its ability to promote both threonine and tyrosine phosphorylation of these (Cowley et al, 1994;Zheng and Guan, 1994). In addition, there is data from our group using SKBR-3 cells (Reddy et al, 1999b) and also other groups using keratinocytes suggesting growth factors that can induce sustained MAPK activation enhances cell migration and invasion (McCawley et al, 1999;Zeigler et al, 1999). To test the hypothesis that MAPK activation enhances cell motility and invasion in non-invasive cells, we stably expressed a constitutively activated MEK1 in non-invasive MCF-7 cells (MEK/MCF-7 cells) and examined its e ect on cell migratory and invasive properties.…”

“…These studies have provided evidence that certain receptor kinases such as EGFR, ERB2, PDGF and others are involved in tumor development (Heldin and Ostman, 1996;McCawley et al, 1999;Reddy et al, 1999b). These growth factors have been shown to stimulate cell migration by activating receptor tyrosine kinase activity, leading to activation of the Ras/ MAPK signal pathways (Hartmann et al, 1994;Klemke et al, 1997).…”

Induction by bombesin of peritoneal metastasis of gastric cancers induced by N -methyl- N ?-nitro- N -nitrosoguanidine in Wistar rats

“…Hellmich et al [23] found that bombesin induced either intracellular calcium oscillations or biphasic elevation in intracellular calcium, and that the activation of mitogen-activated protein kinase (MAPK) kinase (MEK) was important for maintaining the elevated intracellular calcium levels induced by bombesin. The MAPK-MEK cascade was closely related to the tumor cell invasion [24]. However, we did not examine the intracellular calcium level induced by bombesin in this animal model.…”