PAI-1 induces cell detachment, downregulates nucleophosmin (B23) and fortilin (TCTP) in LnCAP prostate cancer cells

  • Authors:
    • Jerzy Jankun
    • Ansari M. Aleem
    • Zofia Specht
    • Rick W. Keck
    • Wieslawa Lysiak-Szydlowska
    • Steven H. Selman
    • Ewa Skrzypczak-Jankun
  • View Affiliations

  • Published online on: July 1, 2007     https://doi.org/10.3892/ijmm.20.1.11
  • Pages: 11-20
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Abstract

Plasminogen activator inhibitor (PAI-1) is an anticancer agent that inhibits plasmin driven proteolysis, limiting angiogenesis and metastasis. In low concentrations it could induce cancer cell motility by interacting with urokinase (uPA), its receptor (uPAR), vitronectin and integrins. Active PAI-1 binds to uPA forming a complex with uPAR, while the latent form of PAI-1 does not. PAI-1 is found in both forms in the circulation. It is not clear which form acts as an anticancer agent and how it interacts with malignant cells. To investigate how these forms reduce angiogenesis or metastasis, we have created PAI-1 cysteine mutants in the active conformation (VLHL PAI-1) with an extended half-life that reaches ≈700 h and its R369A mutant, which has an active conformation but cannot bind to uPA (VLHLNS PAI-1). Both VLHL PAI-1s convert into the latent form when treated with a reducing agent (DTT) that breaks disulfide bridges. Unexpectedly, during routine investigation of LnCAP cell proliferation, we have found that cells detach from the culture vessels regardless of PAI-1 conformation or activity. Further investigation showed that treatment of cancer cells with VLHL PAI-1 downregulated nucleophosmin, while all forms of PAI-1 downregulated fortilin. These two proteins are implicated in important cellular processes (cell growth, cell cycle, malignant transformation). This suggests that PAI-1, in addition to its well-known anticancer properties, plays an important role in cell signaling. 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.

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July 2007
Volume 20 Issue 1

Print ISSN: 1107-3756
Online ISSN:1791-244X

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APA
Jankun, J., Aleem, A.M., Specht, Z., Keck, R.W., Lysiak-Szydlowska, W., Selman, S.H., & Skrzypczak-Jankun, E. (2007). PAI-1 induces cell detachment, downregulates nucleophosmin (B23) and fortilin (TCTP) in LnCAP prostate cancer cells. International Journal of Molecular Medicine, 20, 11-20. https://doi.org/10.3892/ijmm.20.1.11
MLA
Jankun, J., Aleem, A. M., Specht, Z., Keck, R. W., Lysiak-Szydlowska, W., Selman, S. H., Skrzypczak-Jankun, E."PAI-1 induces cell detachment, downregulates nucleophosmin (B23) and fortilin (TCTP) in LnCAP prostate cancer cells". International Journal of Molecular Medicine 20.1 (2007): 11-20.
Chicago
Jankun, J., Aleem, A. M., Specht, Z., Keck, R. W., Lysiak-Szydlowska, W., Selman, S. H., Skrzypczak-Jankun, E."PAI-1 induces cell detachment, downregulates nucleophosmin (B23) and fortilin (TCTP) in LnCAP prostate cancer cells". International Journal of Molecular Medicine 20, no. 1 (2007): 11-20. https://doi.org/10.3892/ijmm.20.1.11