title: 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.affiliation: Division of Pediatric Neurosurgery, Stanley Manne Children's Research Institute, Ann & Robert H Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.|Falk Brain Tumor Center, Ann & Robert H Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: G
authors.initials: G
authors.lastname: Xi
authors.affiliation: Division of Pediatric Neurosurgery, Stanley Manne Children's Research Institute, Ann & Robert H Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: E
authors.initials: E
authors.lastname: Hayes
authors.affiliation: Division of Pediatric Neurosurgery, Stanley Manne Children's Research Institute, Ann & Robert H Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: R
authors.initials: R
authors.lastname: Lewis
authors.affiliation: Division of Pediatric Neurosurgery, Stanley Manne Children's Research Institute, Ann & Robert H Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.|Development Biology Program, Stanley Manne Children's Research Institute, Ann & Robert H Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: S
authors.initials: S
authors.lastname: Ichi
authors.affiliation: Department of Biological Sciences, Purdue University Calumet, Hammond, IN, USA.
authors.forename: B
authors.initials: B
authors.lastname: Mania-Farnell
authors.affiliation: Division of Pediatric Neurosurgery, Stanley Manne Children's Research Institute, Ann & Robert H Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.|Development Biology Program, Stanley Manne Children's Research Institute, Ann & Robert H Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: K
authors.initials: K
authors.lastname: Shim
authors.affiliation: Division of Pediatric Neurosurgery, Stanley Manne Children's Research Institute, Ann & Robert H Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.|Development Biology Program, Stanley Manne Children's Research Institute, Ann & Robert H Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: T
authors.initials: T
authors.lastname: Takao
authors.affiliation: Division of Pediatric Neurosurgery, Stanley Manne Children's Research Institute, Ann & Robert H Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.|Development Biology Program, Stanley Manne Children's Research Institute, Ann & Robert H Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: E
authors.initials: E
authors.lastname: Allender
authors.affiliation: Division of Pediatric Neurosurgery, Stanley Manne Children's Research Institute, Ann & Robert H Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.|Development Biology Program, Stanley Manne Children's Research Institute, Ann & Robert H Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: C S
authors.initials: CS
authors.lastname: Mayanil
authors.affiliation: Division of Pediatric Neurosurgery, Stanley Manne Children's Research Institute, Ann & Robert H Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.|Falk Brain Tumor Center, Ann & Robert H Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: T
authors.initials: T
authors.lastname: Tomita
mesh_terms: D000071916:AC133 Antigen; D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D015703:Antigens, CD / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor / Q000187:drug effects; D051747:DNA-Activated Protein Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000071916:AC133 Antigen; D018435:ATP Binding Cassette Transporter, Subfamily B; D015703:Antigens, CD; D000970:Antineoplastic Agents; D051747:DNA-Activated Protein Kinase; D004317:Doxorubicin; D004791:Enzyme Inhibitors; D006023:Glycoproteins; D016328:NF-kappa B; D009687:Nuclear Proteins; D010455:Peptides; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; C513055:ABCB1 protein, human; C000606023:PROM1 protein, human; C497263:PRKDC protein, human
references.citation: Lancet Oncol. 2009 May;10 (5):459-66
references.pmid: 19269895
references.citation: J Clin Invest. 2013 Oct;123(10):4131-3
references.pmid: 24084745
references.citation: Mol Cell Biochem. 2010 Jul;340(1-2):265-73
references.pmid: 20224986
references.citation: J Biol Chem. 2007 Jul 20;282(29):21206-12
references.pmid: 17513297
references.citation: Cell Mol Neurobiol. 2009 Sep;29(6-7):845-58
references.pmid: 19288188
references.citation: Cancer Res. 1988 Nov 1;48(21):5927-32
references.pmid: 2901906
references.citation: J Neurosci. 2010 Jul 28;30(30):10096-111
references.pmid: 20668194
references.citation: Proc Natl Acad Sci U S A. 2013 Apr 23;110(17 ):6829-34
references.pmid: 23569237
references.citation: Cell Cycle. 2009 Sep 15;8(18):2936-44
references.pmid: 19713741
references.citation: Cancer Lett. 2008 Jan 18;259(1):111-8
references.pmid: 18006147
references.citation: Acta Biochim Biophys Sin (Shanghai). 2010 Sep;42(9):593-602
references.pmid: 20705681
references.citation: Nat Rev Cancer. 2005 Apr;5(4):275-84
references.pmid: 15803154
references.citation: Biochim Biophys Acta. 1973 Oct 25;323(3):466-83
references.pmid: 4796512
references.citation: Neoplasma. 2012;59(3):248-56
references.pmid: 22329846
references.citation: Nat Rev Drug Discov. 2005 Dec;4(12):988-1004
references.pmid: 16341064
references.citation: Proc Natl Acad Sci U S A. 2009 Sep 22;106(38):16281-6
references.pmid: 19805294
references.citation: Oncogene. 2002 Mar 27;21(13):1945-54
references.pmid: 11960367
references.citation: Biochemistry. 2007 May 15;46(19):5766-75
references.pmid: 17441731
references.citation: Science. 1988 Oct 28;242(4878):540-6
references.pmid: 3140380
references.citation: Nanomedicine. 2014 Feb;10(2):381-91
references.pmid: 23916888
references.citation: Cancer Res. 1992 Jun 1;52(11):3157-63
references.pmid: 1591727
references.citation: Eur J Pharm Sci. 2006 Dec;29(5):426-34
references.pmid: 17010577
references.citation: Biochem Pharmacol. 2014 Mar 1;88(1):58-65
references.pmid: 24418411
references.citation: J Neurosurg. 1991 Mar;74(3):460-6
references.pmid: 1671590
references.citation: Proc Natl Acad Sci U S A. 1999 Mar 2;96(5):2110-5
references.pmid: 10051603
references.citation: Int J Cancer. 2014 Mar 15;134(6):1270-8
references.pmid: 24105655
references.citation: Histopathology. 2011 Oct;59(4):763-75
references.pmid: 22014056
references.citation: Oncologist. 2006 Feb;11(2):165-80
references.pmid: 16476837
references.citation: Neuro Oncol. 2011 Jan;13(1):70-83
references.pmid: 20978004
references.citation: Stem Cell Rev. 2008 Sep;4(3):203-10
references.pmid: 18595010
references.citation: Methods Enzymol. 1981;77:231-5
references.pmid: 7329301
references.citation: J Neurooncol. 1994;20(2):165-76
references.pmid: 7807193
references.citation: Oncogene. 2005 Jul 21;24(31):4965-74
references.pmid: 15897897
references.citation: Biochem Biophys Res Commun. 1998 Jun 9;247(1):79-83
references.pmid: 9636658
references.citation: Science. 1995 Feb 24;267(5201):1183-5
references.pmid: 7855602
references.citation: Cancer Res. 1987 Oct 1;47(19):5141-8
references.pmid: 2441861
references.citation: Mol Cancer. 2010 Jul 28;9:199
references.pmid: 20663232
references.citation: Oncogenesis. 2012 Jun 04;1:e12
references.pmid: 23552696
references.citation: Leukemia. 2007 Mar;21(3):427-38
references.pmid: 17215852
references.citation: Cancer Res. 2013 Jan 1;73(1):406-16
references.pmid: 23135908
references.citation: N Engl J Med. 2006 Sep 21;355(12):1253-61
references.pmid: 16990388
references.citation: J Neurosurg. 2013 Nov;119(5):1145-55
references.pmid: 23991844
references.citation: Int J Cancer. 1994 Sep 15;58(6):860-4
references.pmid: 7927879
references.citation: Mol Cancer. 2006 Dec 02;5:67
references.pmid: 17140455
references.citation: J Pharm Pharmacol. 2013 Feb;65(2):157-70
references.pmid: 23278683
references.citation: Mol Cancer Res. 2009 Jul;7(7):989-99
references.pmid: 19609002
references.citation: Cancer Res. 1989 Jun 1;49(11):2988-93
references.pmid: 2566376
references.citation: Nature. 2006 Dec 7;444(7120):756-60
references.pmid: 17051156
references.citation: Cancer Res. 1978 Jun;38(6):1785-91
references.pmid: 647687
references.citation: Clin Cancer Res. 2009 Oct 15;15(20):6314-20
references.pmid: 19808869
references.citation: Oncogene. 2013 Feb 28;32(9):1144-54
references.pmid: 22525278
references.citation: N Engl J Med. 2005 Mar 10;352(10 ):997-1003
references.pmid: 15758010
references.citation: J Neurooncol. 1998 Oct;40(1):11-8
references.pmid: 9874181
references.citation: Transl Cancer Res. 2012 Jun 1;1(1):22-34
references.pmid: 22943041
references.citation: J Neurooncol. 2009 Aug;94(1):1-19
references.pmid: 19468690
references.citation: Nat Rev Cancer. 2002 Jan;2(1):48-58
references.pmid: 11902585
references.citation: Biochem Biophys Res Commun. 2013 Apr 19;433(4):496-501
references.pmid: 23524267
references.citation: Cancer Metastasis Rev. 2007 Mar;26(1):39-57
references.pmid: 17323127
references.citation: PLoS One. 2013;8(1):e54193
references.pmid: 23349823
references.citation: Br J Cancer. 1992 Apr;65(4):538-44
references.pmid: 1348623
references.citation: Mol Cancer Res. 2010 Aug;8(8):1105-15
references.pmid: 20663862
references.citation: Cancer Invest. 2009 Nov;27(9):901-8
references.pmid: 19832037
references.citation: Proc Natl Acad Sci U S A. 1992 Mar 1;89(5):1875-9
references.pmid: 1542686
references.citation: Int J Cancer. 2002 Mar 10;98 (2):173-80
references.pmid: 11857404
references.citation: Cancer Invest. 2008 Nov;26(9):883-9
references.pmid: 18798065
references.citation: Drug Resist Updat. 2002 Dec;5(6):234-48
references.pmid: 12531180
references.citation: Brain Pathol. 2003 Oct;13(4):482-94
references.pmid: 14655754