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Journal of Neuro-Oncology

, Volume 107, Issue 1, pp 69–80 | Cite as

uPAR and cathepsin B downregulation induces apoptosis by targeting calcineurin A to BAD via Bcl-2 in glioma

  • Rama Rao Malla
  • Sreelatha Gopinath
  • Christopher S. Gondi
  • Kiranmai Alapati
  • Dzung H. Dinh
  • Andrew J. Tsung
  • Jasti S. Rao
Laboratory Investigation - Human/Animal Tissue

Abstract

Cathepsin B and urokinase plasminogen activator receptor (uPAR) are postulated to play key roles in glioma invasion. Calcineurin is one of the key regulators of mitochondrial-dependent apoptosis, but its mechanism is poorly understood. Hence, we studied subcellular localization of calcineurin after transcriptional downregulation of uPAR and cathepsin B in glioma. In the present study, efficient downregulation of uPAR and cathepsin B increased the translocation of calcineurin A from the mitochondria to the cytosol, decreased pBAD (S136) expression and its interaction with 14-3-3ζ and increased the interaction of BAD with Bcl-xl. Co-depletion of uPAR and cathepsin B induced mitochondrial translocation of BAD, activation of caspase 3 as well as PARP and cytochrome c and SMAC release. These effects were inhibited by FK506 (10 μM), a specific inhibitor of calcineurin. Calcineurin A was co-localized and also co-immunoprecipitated with Bcl-2. This interaction decreased with co-depletion of uPAR and cathepsin B and also with Bcl-2 inhibitor, HA 14-1 (20 μg/ml). Altered localization and interaction of calcineurin A with Bcl-2 was also observed in vivo when uPAR and cathepsin B were downregulated. In conclusion, downregulation of uPAR and cathepsin B induced apoptosis by targeting calcineurin A to BAD via Bcl-2 in glioma.

Keywords

Calcineurin BAD Bcl2 Glioma 

Notes

Acknowledgment

This research was supported by National Institutes of Health, CA116708 (to JSR). Contents of this manuscript are solely the responsibility of the authors and do not necessarily represent the official views of NIH.

Supplementary material

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Copyright information

© Springer Science+Business Media, LLC. 2011

Authors and Affiliations

  • Rama Rao Malla
    • 1
  • Sreelatha Gopinath
    • 1
  • Christopher S. Gondi
    • 1
  • Kiranmai Alapati
    • 1
  • Dzung H. Dinh
    • 2
  • Andrew J. Tsung
    • 2
  • Jasti S. Rao
    • 1
    • 2
  1. 1.Department of Cancer Biology and PharmacologyUniversity of Illinois College of Medicine at PeoriaPeoriaUSA
  2. 2.Department of NeurosurgeryUniversity of Illinois College of Medicine at PeoriaPeoriaUSA

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