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.
Lademann
Ulrik
U
Institute of Veterinary Pathobiology, The Royal Veterinary and Agricultural University, DK-1870 Copenhagen, Denmark. ul@kvl.dk
Rømer
Maria U
MU
Jensen
Peter Buhl
PB
Hofland
Kenneth F
KF
Larsen
Lise
L
Christensen
Ib Jarle
IJ
Brünner
Nils
N
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D015153:Blotting, Western; D002471:Cell Transformation, Neoplastic; D004305:Dose-Response Relationship, Drug; D005047:Etoposide / Q000494:pharmacology; D005347:Fibroblasts / Q000473:pathology*; D005354:Fibrosarcoma / Q000188:drug therapy / Q000473:pathology*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology*; D008297:Male; D051379:Mice; D017395:Plasminogen Activator Inhibitor 1 / Q000172:deficiency / Q000235:genetics*
D000972:Antineoplastic Agents, Phytogenic; D017395:Plasminogen Activator Inhibitor 1; D005047:Etoposide