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.
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.
Department of Biochemistry, School of Pharmacy, Tokyo University of Pharmacy and Life Science, Hachioji, Japan.
Y
Y
Sawaji
T
T
Sato
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M
Seiki
A
A
Ito
D003994:Bucladesine / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000378:metabolism*; D018093:Gelatinases / Q000378:metabolism*; D018869:Heat-Shock Response; D006801:Humans; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
D004792:Enzyme Precursors; D005576:Colforsin; D003994:Bucladesine; D000242:Cyclic AMP; D018093:Gelatinases; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; C069860:progelatinase