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Inhibition of protein disulfide isomerase in glioblastoma causes marked downregulation of DNA repair and DNA damage response genes
- Source :
- Theranostics
- Publication Year :
- 2019
- Publisher :
- Ivyspring International Publisher, 2019.
-
Abstract
- Aberrant overexpression of endoplasmic reticulum (ER)-resident oxidoreductase protein disulfide isomerase (PDI) plays an important role in cancer progression. In this study, we demonstrate that PDI promotes glioblastoma (GBM) cell growth and describe a class of allosteric PDI inhibitors that are selective for PDI over other PDI family members. Methods: We performed a phenotypic screening triage campaign of over 20,000 diverse compounds to identify PDI inhibitors cytotoxic to cancer cells. From this screen, BAP2 emerged as a lead compound, and we assessed BAP2-PDI interactions with gel filtration, thiol-competition assays, and site-directed mutagenesis studies. To assess selectivity, we compared BAP2 activity across several PDI family members in the PDI reductase assay. Finally, we performed in vivo studies with a mouse xenograft model of GBM combining BAP2 and the standard of care (temozolomide and radiation), and identified affected gene pathways with nascent RNA sequencing (Bru-seq). Results: BAP2 and related analogs are novel PDI inhibitors that selectively inhibit PDIA1 and PDIp. Though BAP2 contains a weak Michael acceptor, interaction with PDI relies on Histidine 256 in the b' domain of PDI, suggesting allosteric binding. Furthermore, both in vitro and in vivo, BAP2 reduces cell and tumor growth. BAP2 alters the transcription of genes involved in the unfolded protein response, ER stress, apoptosis and DNA repair response. Conclusion: These results indicate that BAP2 has anti-tumor activity and the suppressive effect on DNA repair gene expression warrants combination with DNA damaging agents to treat GBM.
- Subjects :
- 0301 basic medicine
inorganic chemicals
DNA Repair
DNA damage
DNA repair
Cell Survival
Transplantation, Heterologous
Drug Evaluation, Preclinical
Protein Disulfide-Isomerases
Medicine (miscellaneous)
Down-Regulation
Antineoplastic Agents
allosteric inhibition
drug discovery
03 medical and health sciences
chemistry.chemical_compound
Mice
0302 clinical medicine
Transcription (biology)
Cell Line, Tumor
cancer
Animals
Humans
Enzyme Inhibitors
Protein disulfide-isomerase
Pharmacology, Toxicology and Pharmaceutics (miscellaneous)
Gene
Protein disulfide isomerase
3. Good health
Cell biology
nervous system diseases
body regions
Disease Models, Animal
030104 developmental biology
Treatment Outcome
chemistry
030220 oncology & carcinogenesis
Cancer cell
Unfolded protein response
Mutagenesis, Site-Directed
Glioblastoma
DNA
Neoplasm Transplantation
Research Paper
DNA Damage
Protein Binding
Subjects
Details
- Language :
- English
- ISSN :
- 18387640
- Volume :
- 9
- Issue :
- 8
- Database :
- OpenAIRE
- Journal :
- Theranostics
- Accession number :
- edsair.doi.dedup.....1ad1fdc19ba53d3dbc183692023c3d7b