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Intracellular Urokinase uPA-PAI-1 Complex: Disruption by Small Molecule Targets Hypoxically Programmed Glioma Cells

Author

Listed:
  • Nagarekha Pasupuleti
  • Anthony Valenzuela
  • Yamini Manohar

    (Departments of Neurology (School of Medicine) and Molecular Biosciences (School of Veterinary Medicine), University of California Davis, USA)

  • Sundeep Dugar

    (Sphaera Pharma Inc., Singapore and Sphaera Pharma Pvt. Ltd., India)

  • Jann Sarkaria

    (Department of Radiation Oncology, Mayo Clinic, USA)

Abstract

High grade gliomas (HGGs) are primary lethal CNS cancers. Elevated protein levels of uPA-PAI-1 complexes are a highly predictive biomarker for a number of highly proliferative solid cancers predisposed to infiltrate and metastasize. We report a new small molecule (Cmpd10357) that rapidly disrupts intracellular uPA-PAI-1 complexes and which temporally corresponds with the relocation of endosomes containing urokinase protein cargo. ‘Mis-trafficking’ of these uPAS endosomes by Cmpd10357 and its parent compound UCD38B triggers AIF-mediated, caspase-independent glioma necrosis. We now identify that Compound10357 and UCD38B disrupt intracellular uPA-PAI-1 complexes to trigger this programmed cancer cell necrosis. This novel drug target suggests a potential functionality for elevated levels of uPA-PAI-1that has been identified in many high grade solid cancers.

Suggested Citation

  • Nagarekha Pasupuleti & Anthony Valenzuela & Yamini Manohar & Sundeep Dugar & Jann Sarkaria, 2018. "Intracellular Urokinase uPA-PAI-1 Complex: Disruption by Small Molecule Targets Hypoxically Programmed Glioma Cells," Open Access Journal of Neurology & Neurosurgery, Juniper Publishers Inc., vol. 7(3), pages 42-59, March.
    • Handle: RePEc:adp:joajnn:v:7:y:2018:i:3:p:42-59
    DOI: 10.19080/OAJNN.2018.07.555712
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    References listed on IDEAS

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    1. Jacques Pouysségur & Frédéric Dayan & Nathalie M. Mazure, 2006. "Hypoxia signalling in cancer and approaches to enforce tumour regression," Nature, Nature, vol. 441(7092), pages 437-443, May.
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