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

Nagarekha Pasupuleti, Anthony Valenzuela, Yamini Manohar, Sundeep Dugar and Jann Sarkaria
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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

Open Access Journal of Neurology & Neurosurgery, 2018, vol. 7, issue 3, 42-59

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.

Keywords: Open Access Journal of Neurology; Journal of Neurology & Neurosurgery; Open Access Journal; juniper publishers; neurology open access journals; journal of neurology; neurology indexed journals; neurology scholarly journals; journal of neurology; neurology journals impact factor; juniper publishers reivew (search for similar items in EconPapers)
Date: 2018
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Persistent link: https://EconPapers.repec.org/RePEc:adp:joajnn:v:7:y:2018:i:3:p:42-59

DOI: 10.19080/OAJNN.2018.07.555712

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