SB203580, a specific inhibitor of p38 mitogen-activated protein kinase, modulates phorbol ester induced regulation of matrix metalloproteinases and tissue inhibitors of metalloproteinases system in D54 human glioblastoma cells

MJ Park, PhD, SH Lee, MD, MS Kim, MS, IC Park, PhD, JH Hur, MS, HC Lee, MS, SH Woo, MS, KH Lee, BS, CH Rhee, MD, SI Hong, MD

Laboratory of Cell Biology, Korea Cancer Center Hospital, Seoul, Nowongu Korea Republic

AIM: Matrix metalloproteinase (MMP)s expression has been postulated to play a central role in rain tumor invasion, however, its underlying mechanism has not yet been fully understood. In the present study, by studying the effect of specific p38 inhibitor, SB203580, on the secretion of MMPs and in vitro invasion of various glioma cells, we attempted to define the role of p38 pathway in the regulation of MMPs/tissue inhibitor of metalloproteinase (TIMP)s system in D54 human glioblastoma cells. Methods: Activation of mitogen activated protein kinase (MAPK)s was determined by Western blot analysis, and MMPs and TIMPs status were analyzed by gelatin zymography and Western blot analysis, and invasion rate of glioma cells were analyzed by modified Boyden chamber assay. Results: Treatment of D54 cells with PMA activated two distinct MAPKs, ERK 1/2 and p38, but not JNK/SAPK. Induction of MMP-9 production and MMP-2 activation by PMA were blocked by SB203580, a specific inhibitor of p38, but not by PD98059, a specific inhibitor of ERK 1/2. In addition, PMA induced down-regulation of TIMP-1 and –2 secretion and up-regulation of the MT1-MMP, a major activator of MMP-2 on the cell surface, were reverted by SB203580 in these cells, PMA-induced increase of in vitro invasion decreased when SB203580 was added to the top chamber of modified Boyden-chamber. Conclusions. These results suggested that activation of p38 by PMA played a central role in the regulation of MMPs/TIMPs system in D54 cells, which has a major role in tumor invasion and metastasis.

KEY WORDS: Key Word Invasion, Protein kinase C, Metastasis.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Metastasis.