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Heat shock-mediated transient increase in intracellular 3′, 5′-cyclic AMP results in tumor specific suppression of membrane type 1-matrix metalloproteinase production and progelatinase A activation

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Abstract

We have previously reported that heat shock suppresses the production and gene expression of membrane type 1-matrix metalloproteinase (MT1-MMP) and thereby inhibits the activation of progelatinase A/proMMP-2 in human fibrosarcoma HT-1080 cells and human squamous carcinoma A431 cells and SAS cells (Sato et al. Biochem Biophys Res Commun 1999; 265: 189–93). In an effort to clarify the heat shock-mediated signal transduction pathways, an intracellular cAMP level was found to be transiently augmented in the heat shocked HT-1080 cells. When HT-1080 cells were pretreated with cAMP elevating reagents, forskolin and dibutyryl cAMP for 4 h instead of heat shock and then maintained in a fresh medium, the production and gene expression of MT1-MMP were similarly suppressed. The MT1-MMP-mediated activation of proMMP-2 was also inhibited in the forskolin- and dibutyryl cAMP-treated HT-1080 cells. Furthermore, the transiently augmented cAMP by forskolin as well as heat shock interfered with in vitro invasive activity of HT-1080 cells. In contrast, in normal human fibroblasts neither heat shock nor cAMP elevating reagents altered the concanavalin A-augmented MT1-MMP production and proMMP-2 activation. These results suggest that a transient increase in intracellular cAMP is a critical signal for heat shock to induce tumor specific-suppression of MT1-MMP production and proMMP-2 activation.

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Authors and Affiliations

  1. Department of Biochemistry, School of Pharmacy, Tokyo University of Pharmacy and Life Science, Horinouchi, Hachioji, Tokyo, 192-0392, Japan

    Yasunobu Sawaji, Takashi Sato & Akira Ito

  2. Department of Cancer Cell Research, Institute of Medical Science, University of Tokyo, Shirokanedai, Minato-ku, Tokyo, 108-0071, Japan

    Motoharu Seiki

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  1. Yasunobu Sawaji
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  2. Takashi Sato
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  3. Motoharu Seiki
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  4. Akira Ito
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Sawaji, Y., Sato, T., Seiki, M. et al. Heat shock-mediated transient increase in intracellular 3′, 5′-cyclic AMP results in tumor specific suppression of membrane type 1-matrix metalloproteinase production and progelatinase A activation. Clin Exp Metastasis 18, 131–138 (2000). https://doi.org/10.1023/A:1006760021997

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