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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
- Source :
- Oncogene. 35:241-250
- Publication Year :
- 2015
- Publisher :
- Springer Science and Business Media LLC, 2015.
-
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.
- Subjects :
- 0301 basic medicine
Cancer Research
Small interfering RNA
ATP Binding Cassette Transporter, Subfamily B
Antineoplastic Agents
DNA-Activated Protein Kinase
Biology
Phosphatidylinositol 3-Kinases
03 medical and health sciences
0302 clinical medicine
Downregulation and upregulation
Antigens, CD
Cell Line, Tumor
Glioma
Genetics
medicine
Humans
Doxorubicin
AC133 Antigen
Enzyme Inhibitors
neoplasms
Molecular Biology
Protein kinase B
PI3K/AKT/mTOR pathway
Glycoproteins
Phosphoinositide-3 Kinase Inhibitors
NF-kappa B
Nuclear Proteins
Cell cycle
medicine.disease
carbohydrates (lipids)
Multiple drug resistance
030104 developmental biology
Drug Resistance, Neoplasm
030220 oncology & carcinogenesis
embryonic structures
Cancer research
Glioblastoma
Peptides
Proto-Oncogene Proteins c-akt
Signal Transduction
medicine.drug
Subjects
Details
- ISSN :
- 14765594 and 09509232
- Volume :
- 35
- Database :
- OpenAIRE
- Journal :
- Oncogene
- Accession number :
- edsair.doi.dedup.....eddfed16b370f6a4a8daace414894864