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

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.

• Authors: G Xi, E Hayes, R Lewis, S Ichi, B Mania-Farnell, K Shim, T Takao, E Allender, C S Mayanil, T Tomita
• Journal: Oncogene (Oncogene) Vol. 35 Issue 2 Pg. 241-50 (Jan 14 2016) ISSN: 1476-5594 [Electronic] England
• PMID: 25823028 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Retracted Publication)

Chemical References

• ABCB1 protein, human
• AC133 Antigen
• ATP Binding Cassette Transporter, Subfamily B
• Antigens, CD
• Antineoplastic Agents
• Enzyme Inhibitors
• Glycoproteins
• NF-kappa B
• Nuclear Proteins
• PROM1 protein, human
• Peptides
• Phosphoinositide-3 Kinase Inhibitors
• Doxorubicin
• DNA-Activated Protein Kinase
• PRKDC protein, human
• Proto-Oncogene Proteins c-akt

Topics

• AC133 Antigen
• ATP Binding Cassette Transporter, Subfamily B (metabolism)
• Antigens, CD (metabolism)
• Antineoplastic Agents (pharmacology)
• Cell Line, Tumor (drug effects)
• DNA-Activated Protein Kinase (antagonists & inhibitors, genetics, metabolism)
• Doxorubicin (pharmacology)
• Drug Resistance, Neoplasm (drug effects)
• Enzyme Inhibitors (pharmacology)
• Glioblastoma (drug therapy, genetics, metabolism)
• Glycoproteins (metabolism)
• Humans
• NF-kappa B (metabolism)
• Nuclear Proteins (antagonists & inhibitors, genetics, metabolism)
• Peptides (metabolism)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors, metabolism)
• Signal Transduction (drug effects)