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CD133 and DNA-PK regulate MDR1 via the PI3K- or Akt-NF-κB pathway in multidrug-resistant glioblastoma cells in vitro

Authors
 G Xi  ;  E Hayes  ;  R Lewis  ;  S Ichi  ;  B Mania-Farnell  ;  K Shim  ;  T Takao  ;  E Allender  ;  CS Mayanil  ;  T Tomita 
Citation
 ONCOGENE, Vol.35(2) : 241-250, 2016 
Journal Title
 ONCOGENE 
ISSN
 0950-9232 
Issue Date
2016
MeSH
AC133 Antigen ; ATP Binding Cassette Transporter, Sub-Family B/metabolism ; Antigens, CD/metabolism* ; Antineoplastic Agents/pharmacology ; Cell Line, Tumor/drug effects ; DNA-Activated Protein Kinase/antagonists & inhibitors ; DNA-Activated Protein Kinase/genetics ; DNA-Activated Protein Kinase/metabolism* ; Doxorubicin/pharmacology ; Drug Resistance, Neoplasm/drug effects ; Enzyme Inhibitors/pharmacology ; Glioblastoma/drug therapy* ; Glioblastoma/genetics ; Glioblastoma/metabolism ; Glycoproteins/metabolism* ; Humans ; NF-kappa B/metabolism ; Nuclear Proteins/antagonists & inhibitors ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism* ; Peptides/metabolism* ; Phosphatidylinositol 3-Kinases/antagonists & inhibitors ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/antagonists & inhibitors ; Proto-Oncogene Proteins c-akt/metabolism ; Signal Transduction/drug effects
Abstract
Chemotherapy is an adjuvant treatment for glioblastomas, however, chemotherapy remains palliative because of the development of multidrug resistance (MDR). Following prolonged chemotherapy, MDR protein 1 (MDR1) and CD133 increase in recurrent glioblastomas. CD133 positive (CD133+) glioma cancer stem-like cells (GCSCs) markedly promote drug resistance and exhibit increased DNA damage repair capability; thus they have a key role in determining tumor chemosensitivity. Although CD133, DNA-dependent protein kinase (DNA-PK), and MDR1 are elevated in CD133+ GCSCs, the relationship among these molecules has not been elucidated. In this study, MDR glioblastoma cell lines were created in response to prolonged doxorubicin chemotherapy. CD133, DNA-PK and MDR1 were markedly elevated in these cells. CD133 and DNA-PK may increase MDR1 via the phosphatidylinositol-3-kinase (PI3K)-Akt signal pathway. PI3K downstream targets Akt and nuclear factor (NF)-κB, which interacts with the MDR1 promoter, were also elevated in these cells. Downregulation of CD133 and DNA-PK by small interfering RNA, or inhibition of PI3K or Akt, decreased Akt, NF-κB and MDR1 expression. The results indicate that CD133 and DNA-PK regulate MDR1 through the PI3K- or Akt-NF-κB signal pathway. Consequently, a novel chemotherapeutic regimen targeting CD133 and DNA-PK in combination with traditional protocols may increase chemotherapeutic efficacy and improve prognosis for individuals who present with glioblastoma.
Full Text
http://www.nature.com/onc/journal/v35/n2/full/onc201578a.html
DOI
10.1038/onc.2015.78
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Neurosurgery (신경외과학교실) > 1. Journal Papers
Yonsei Authors
Shim, Kyu Won(심규원) ORCID logo https://orcid.org/0000-0002-9441-7354
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/146532
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