Genomes and Genes
Genetically Engineered PAI1 for Anti-cancer Therapy
Principal Investigator: Jerzy Jankun
Abstract: Proteolytic activity driven by urokinase plasminogen activator (uPA) is commonly recognized as a critical factor in metastasis. Reduction of proteolytic activity has been proposed as a cancer treatment option; uPA inhibitors could be utilized as a cancer treatment if used prior to the onset of the metastatic process. Moreover, uPA inhibitors have been recently shown to reduce tumor growth as well. We have found that uPA inhibitors reduce angiogenesis (uPA is overexpressed on tip of capillary vessels) and thereby reduce tumor size. The ultimate goal of this proposal is to identify novel inhibitors of uPA suitable for cancer treatment. In this study we want make use of plasminogen activator inhibitor (PAI-1), which will be genetically engineered to introduce novel and desired properties to this protein. These properties include: long half-life (wild PAI-1 converts into its latent form in approximately 2h), lack of vitronectin binding capability (PAI-1 binds to this protein and this property could increase motility of cancer cells), and uPA specificity (PAI-1 is a non-specific inhibitor of both uPA and tPA). The urokinase is involved in pericellular malignant proteolysis, while tPA mainly mediates physiologically needed intravascular thrombolysis and that function ought to be preserved. Lastly, these altered forms of PAI-1 will be combined and tested for anti-uPA and anti-angiogenic activity. The metastatic process and angiogenesis are driven by the urokinase plasminogen system and matrix metallo proteinases (MMPs). In some clinical studies of advanced cancers, inhibition of MMPs showed promise, while in other studies they did not. The efficacy of anti-angiogenic agents would probably be best in remission after traditional chemotherapy, or in combination with cytotoxic agents and possibly with combinations of urokinase and MMPs inhibitors. In addition, the best results can perhaps be gained in adjuvant therapy or in early stages of cancer, when the tumor burden is minimal. Our future efforts are directed toward these goals.
Funding Period: 2004-08-01 - 2006-07-31
more information: NIH RePORT
- Aspirin blocks binding of photosensitizer SnET2 into human serum albumin: implications for photodynamic therapyE Skrzypczak-Jankun
Urology Research Center, Department of Urology, Medical College of Ohio, Toledo, OH 43614, USA
Int J Mol Med 15:777-83. 2005..This observation could be exploited to improve photo-efficiency of SnET2 by finding drugs that could compete with the photosensitizer for binding into Sudlow Site I of HSA...
- Plasminogen activator inhibitor-1 is locked in active conformation and polymerizes upon binding ligands neutralizing its activityJerzy Jankun
Urology Research Center, Medical University of Ohio, Toledo, 43614, USA
Int J Mol Med 17:437-47. 2006..The polymerization of PAI-1 reduces PAI-1 activity by encapsulating the critical RCL fragment inside the formed PAI-1/PAI-1 polymers...
- Synthetic curcuminoids modulate the arachidonic acid metabolism of human platelet 12-lipoxygenase and reduce sprout formation of human endothelial cellsJerzy Jankun
Urology Research Center, Medical University of Ohio, 3065 Arlington, Toledo, OH 43614 5807, USA
Mol Cancer Ther 5:1371-82. 2006..This universal event for all tested lipoxygenase inhibitors suggests that the inhibition of sprout formation was most likely due to the inhibition of human P-12-LOX but not other cancer-related pathways...
- Effect of crystal freezing and small-molecule binding on internal cavity size in a large protein: X-ray and docking studies of lipoxygenase at ambient and low temperature at 2.0 A resolutionE Skrzypczak-Jankun
Urology Research Center, Medical University of Ohio, Toledo, OH 43614, USA
Acta Crystallogr D Biol Crystallogr 62:766-75. 2006....
- Nutraceutical inhibitors of urokinase: potential applications in prostate cancer prevention and treatmentJerzy Jankun
Urology Research Center, Medical University of Ohio, Department of Urology, Toledo, OH 43614 5807, USA
Oncol Rep 16:341-6. 2006..If true, a proper diet rich in uPA-inhibiting nutraceuticals might support the prevention of prostrate cancer and be a supportive tool in prostate cancer treatment...
- PAI-1 induces cell detachment, downregulates nucleophosmin (B23) and fortilin (TCTP) in LnCAP prostate cancer cellsJerzy Jankun
Urology Research Center, University of Toledo, Health Science Campus, Toledo, OH 43614 5807, USA
Int J Mol Med 20:11-20. 2007..We hope that by exploring PAI-1's structure and function we might be able to understand and separate the different effects of PAI-1 on cancer cells and develop more effective therapeutic strategies in cancer treatment...
- Highly stable plasminogen activator inhibitor type one (VLHL PAI-1) protects fibrin clots from tissue plasminogen activator-mediated fibrinolysisJerzy Jankun
Urology Research Center, Health Science Campus, University of Toledo, Toledo, OH 43614 5807, USA
Int J Mol Med 20:683-7. 2007....