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Induction of Tissue-type Plasminogen Activator by Ionizing Radiation in Human Malignant Melanoma Cells¹

Department of Radiation Oncology, Division of Cancer Biology, University of Michigan, Ann Arbor, Michigan 48109 [D. A. B., M. W.], and Dana-Farber Cancer Institute, Division of Cancer Genetics, Harvard University, Boston, Massachusetts 02115 [S. W. L.]

Two differently timed extracellular and intracellular enzymatic and mRNA peaks of tissue-type plasminogen activator (t-PA) were induced following ionizing radiation. The first peak appeared within 10 min following X-irradiation but rapidly declined. The appearance of early t-PA mRNA transcripts and enzymatic activity were not prevented by actinomycin D treatment. In contrast, cycloheximide prevented the early, minor enzymatic induction peak of t-PA. Stabilization of t-PA mRNA transcripts appears to be an early initial response of human cells to ionizing radiation, since the synthesis of new mRNA transcripts within the first 30 min was not observed via nuclear run-on analyses.

Nearly 12 h following X-irradiation, a second major enzymatic peak of t-PA was observed. Cycloheximide or actinomycin D treatments blocked the later t-PA response. t-PA mRNA levels were induced > 100-fold in 4 h by ionizing radiation as assayed via Northern or nuclear run-on analyses. During the major induction period, t-PA mRNA transcripts reached their maximum levels at 4–8 h, and intracellular enzyme levels accumulated 6–8 h after X-irradiation. Unirradiated U1-Mel cells demonstrated only low basal levels of t-PA mRNA and enzymatic activity. Similar induction responses were found following UV-irradiation or 12-O-tetradecanoyl-phorbol-13-acetate (PMA) treatments.

Normal human fibroblast (i.e., GM 2936B, GM2907A, and IMR-90) cells also demonstrated the induction of t-PA, although only one later enzymatic peak was detected. The induction of t-PA mRNA levels and intracellular and extracellular enzymatic activities for these cells were 50-fold lower than with U1-Mel cells given equitoxic doses of X-rays. Differential expression of t-PA in some tumor as compared to normal tissues may be utilized in future chemotherapeutic regimens.

¹ This work was supported by a grant from the American Cancer Society (PDT-412).

² To whom requests for reprints should be addressed, at Department of Radiation Oncology, Division of Cancer Biology, University of Michigan, 1331 East Ann Street, Rm 4131, Ann Arbor, MI 48109.

Received 2/22/91. Accepted 8/ 8/91.

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