Malignant transformation of wild-type but not plasminogen activator inhibitor-1 gene-deficient fibroblasts decreases cellular sensitivity to chemotherapy-mediated apoptosis

Plasminogen activator inhibitor-1 (PAI-1) inhibits the activation of the plasminogen activator system, the latter being involved in cancer growth and dissemination. Interestingly, PAI-1 is elevated in many solid tumours and this elevation has consistently been shown to be associated with shorter length of patient survival. This study aims to determine whether PAI-1 contributes to cancer cell growth by inhibiting apoptosis of tumour cells. It is shown that spontaneous transformation decreases cellular sensitivity to chemotherapy-mediated apoptosis of wild-type, but not PAI-1 gene-deficient, fibrosarcomas. PAI-1 gene-deficient and wild-type mice displayed similar sensitivity to treatment with etoposide, suggesting a differential effect of PAI-1 expression between cancer cells and normal cells. Thus, since PAI-1 appears to be an important factor in regulating apoptosis in cancer cells but not in normal cells, inhibitors of PAI-1 might be useful as sensitising pre-treatment for subsequent apoptosis-inducing anti-cancer therapy. (c) 2005 Elsevier Ltd. All rights reserved.