title: DT(270-326) , a Truncated Diphtheria Toxin, Increases Blood-Tumor Barrier Permeability by Upregulating the Expression of Caveolin-1.
abstract: The nontoxic mutant of diphtheria toxin (DT) has been demonstrated to act as a receptor-specific carrier protein to delivery drug into brain. Recent research showed that the truncated "receptorless" DT was still capable of being internalized into cells. This study investigated the effects and potential mechanisms of DT(270-326) , a truncated "receptorless" DT, on the permeability of the blood-tumor barrier (BTB).
  
  
  
  BTB and GECs were subjected to DT(270-326) treatment. HRP flux assays, immunofluorescent, co-immunoprecipitation, Western blot, CCK-8, and Flow cytometry analysis were used to evaluate the effects of DT(270-326) administration.
  
  
  
  Our results revealed that 5 μM of DT(270-326) significantly increased the permeability of BTBin vitro, which reached its peak at 6 h. The permeability was reduced by pretreatment with filipinIII. DT(270-326) co-localized and interacted with caveolin-1 via its caveolin-binding motif. The mRNA and protein expression levels of caveolin-1 were identical with the changes of BTB permeability. The upregulated expression of caveolin-1 was associated with Src kinase-dependent tyrosine phosphorylation of caveolin-1, which subsequently induced phosphorylation and inactivation of the transcription factor Egr-1. The combination of DT(270-326) with doxorubicin significantly enhanced the loss of cell viability and apoptosis of U87 glioma cells in contrast to doxorubicin alone.
  
  
  
  DT(270-326) might provide a novel strategy to increase the delivery of macromolecular therapeutic agents across the BTB.
authors: Department of Neurobiology, College of Basic Medicine, China Medical University, Shenyang, China.|Institute of Pathology and Pathophysiology, China Medical University, Shenyang, China.
authors: Yang
authors: Y
authors: Lin
authors: Department of Neurobiology, College of Basic Medicine, China Medical University, Shenyang, China.|Institute of Pathology and Pathophysiology, China Medical University, Shenyang, China.
authors: Ping
authors: P
authors: Wang
authors: Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, China.
authors: Yun-Hui
authors: YH
authors: Liu
authors: Department of Neurology, First Affiliated Hospital of China Medical University, Shenyang, China.
authors: Xiu-Li
authors: XL
authors: Shang
authors: Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, China.
authors: Liang-Yu
authors: LY
authors: Chen
authors: Department of Neurobiology, College of Basic Medicine, China Medical University, Shenyang, China.|Institute of Pathology and Pathophysiology, China Medical University, Shenyang, China.
authors: Yi-Xue
authors: YX
authors: Xue
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002199:Capillary Permeability / Q000187:drug effects* / Q000235:genetics; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D004167:Diphtheria Toxin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000473:pathology / Q000648:ultrastructure; D006735:Horseradish Peroxidase / Q000493:pharmacokinetics; D006801:Humans; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D051789:Proto-Oncogene Protein c-fli-1 / Q000235:genetics / Q000378:metabolism; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013997:Time Factors; D057900:Transcytosis / Q000187:drug effects* / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects* / Q000235:genetics
chemical_list: D000903:Antibiotics, Antineoplastic; D051242:Caveolin 1; D004167:Diphtheria Toxin; C497426:Fli1 protein, mouse; D051789:Proto-Oncogene Protein c-fli-1; D006735:Horseradish Peroxidase; D016392:Proto-Oncogene Proteins pp60(c-src)
keywords: Blood-Tumor Barrier; Caveolin-1; Egr-1; Src; Truncated diphtheria toxin