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J. Biol. Chem., Vol. 280, Issue 12, 10938-10944, March 25, 2005

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Acidic Extracellular pH Induces Matrix Metalloproteinase-9 Expression in Mouse Metastatic Melanoma Cells through the Phospholipase D-Mitogen-activated Protein Kinase Signaling^*

Yasumasa Kato¶||, Charles A. Lambert**, Alain C. Colige**, Pierre Mineur**, Agnés Noël, Francis Frankenne, Jean-Michel Foidart, Masaya Baba, Ryu-Ichiro Hata¶, Kaoru Miyazaki, and Mamoru Tsukuda

From the Departments of Otolaryngology and Urology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan, Laboratories of ^**Connective Tissue Biology and Tumor and Developmental Biology, University of Liège, B-4000 Liège, Belgium, ^¶Department of Biochemistry and Molecular Biology, Kanagawa Dental College, Yokosuka 238-8580, Japan, and Division of Cell Biology, Kihara Institute for Biological Research, Yokohama City University, Yokohama 244-0813, Japan

The extracellular pH (pHe) of tumor tissues is often acidic, which can induce the expression of several proteins. We previously showed that production of matrix metalloproteinase-9 (MMP-9) was induced by culturing cells at acidic pHe (5.4–6.5). Here we have investigated the signal transduction pathway by which acidic pHe induces MMP-9 expression. We found that acidic pHe (5.9) activated phospholipase D (PLD), and inhibition of PLD activity by 1-butanol and Myr-ARF6 suppressed the acidic pHe-induced MMP-9 expression. Exogenous PLD, but not phosphatidylinositol-specific PLC or PLA₂, mimicked MMP-9 induction by acidic pHe. Western blot analysis revealed that acidic pHe increased the steady-state levels of phosphorylated extracellular signal-regulated kinases 1/2 and p38 and that the PLD inhibitors suppressed these increases. Using 5'-deletion mutant constructs of the MMP-9 promoter, we found that the acidic pHe-responsive region was located at nucleotide –670 to –531, a region containing the NFB binding site. A mutation into the NFB binding site reduced, but not completely, the acidic pHe-induced MMP-9 promoter activity, and NFB activity was induced by acidic pHe. Pharmacological inhibitors specific for mitogen-activated protein kinase kinase 1/2 (PD098059) and p38 (SB203580) attenuated the acidic pHe-induced NFB activity and MMP-9 expression. These data suggest that PLD, mitogen-activated protein kinases (extracellular signal-regulated kinases 1/2 and p38), and NFB mediate the acidic pHe signaling to induce MMP-9 expression. A transcription factor(s) other than NFB may also be involved in the MMP-9 expression.

Received for publication, October 4, 2004 , and in revised form, January 14, 2005.

^* This work was supported in part by a grant-in-aid for Bioventure Research from the Ministry of Education, Science, Culture, Sports, Science, and Technology of Japan and by grants-in-aid for Scientific Research (B) and (C) from the Japan Society for the Promotion of Science, Japan. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, Kanagawa Dental College, Yokosuka 238-8580, Japan. Tel.: 81-46-822-8840; Fax: 81-46-822-8839; E-mail: yasumasa{at}kdcnet.ac.jp.

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