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Mitogen‐activated protein kinase (MAPK) regulates the expression of progelatinase B (MMP‐9) in breast epithelial cells
Author(s) -
Reddy Kaladhar B.,
Krueger Joseph S.,
B. Kondapaka Sudhir,
Diglio Clement A.
Publication year - 1999
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/(sici)1097-0215(19990719)82:2<268::aid-ijc18>3.0.co;2-4
Subject(s) - mapk/erk pathway , wortmannin , cancer research , epidermal growth factor , microbiology and biotechnology , cell growth , biology , kinase , protein kinase a , signal transduction , mek inhibitor , chemistry , cell culture , pi3k/akt/mtor pathway , biochemistry , genetics
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.