title: Plasminogen activator inhibitor 1 protects fibrosarcoma cells from etoposide-induced apoptosis through activation of the PI3K/Akt cell survival pathway.
abstract: High levels of plasminogen activator inhibitor (PAI-1) in tumors are associated with poor prognosis in several cancer types, and the reason for this association is not fully understood. Plasminogen activator inhibitor 1 has been suggested to contribute to tumor growth by protecting cancer cells from apoptosis, and we have previously shown that wild type murine fibrosarcoma cells are significantly more resistant to apoptosis induced by chemotherapy than PAI-1-deficient fibrosarcoma cells. Here, we further investigated the molecular mechanisms underlying the antiapoptotic function of PAI-1 focusing on the phosphatidylinositol 3-phosphate kinase (PI3K)/Akt cell survival pathway. We demonstrate that the activation level of the Akt cell survival pathway is reduced in PAI-1-deficient cells. Inhibition of either PI3K or Akt by synthetic inhibitors sensitized the wild type but not the PAI-1-deficient cells to etoposide-induced cell death. More importantly, reintroduction of PAI-1 expression in PAI-1-deficient cells induced an increase in Akt activity and protection against etoposide-induced apoptosis. Concordantly, silencing of PAI-1 by RNA interference in wild type fibrosarcoma cells decreased the level of active Akt, and this was accompanied by a sensitization of the cells to etoposide-induced cell death. Altogether, our data suggest that PAI-1 influences sensitivity to etoposide-induced apoptosis through the PI3K/Akt cell survival pathway by acting upstream of PI3K and Akt. This points to PAI-1 as a possible therapeutic target in cancer diseases where PAI-1 inhibits chemotherapy-induced apoptosis.
authors.affiliation: Department of Veterinary Pathobiology, Section for Biomedicine, Faculty of Life Sciences, University of Copenhagen, Ridebanevej 9, DK-1870 Frederiksberg C, Copenhagen, Denmark.
authors.forename: Maria U
authors.initials: MU
authors.lastname: Rømer
authors.forename: Lise
authors.initials: L
authors.lastname: Larsen
authors.forename: Hanne
authors.initials: H
authors.lastname: Offenberg
authors.forename: Nils
authors.initials: N
authors.lastname: Brünner
authors.forename: Ulrik A
authors.initials: UA
authors.lastname: Lademann
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002867:Chromones / Q000008:administration & dosage / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D004789:Enzyme Activation / Q000235:genetics; D005047:Etoposide / Q000494:pharmacology / Q000627:therapeutic use*; D005354:Fibrosarcoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009025:Morpholines / Q000008:administration & dosage / Q000494:pharmacology; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D034741:RNA, Small Interfering / Q000494:pharmacology / Q000627:therapeutic use; D058258:Serpin E2; D015843:Serpins / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D002867:Chromones; D005047:Etoposide; D009025:Morpholines; D051058:Oncogene Protein v-akt; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D034741:RNA, Small Interfering; D058258:Serpin E2; D015843:Serpins; C511869:Serpine2 protein, mouse; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one