Overcoming adaptive resistance in mucoepidermoid carcinoma through inhibition of the IKK-β/IκBα/NFκB axis.
Patients with mucoepidermoid carcinoma (MEC) experience low survival rates and high morbidity following treatment, yet the intrinsic resistance of MEC cells to ionizing radiation (IR) and the mechanisms underlying acquired resistance remain unexplored. Herein, we demonstrated that low doses of IR intrinsically activated NFκB in resistant MEC cell lines. Moreover, resistance was significantly enhanced in IR-sensitive cell lines when NFκB pathway was stimulated. Pharmacological inhibition of the IKK-β/IκBα/NFκB axis, using a single dose of FDA-approved Emetine, led to a striking sensitization of MEC cells to IR and a reduction in cancer stem cells. We achieved a major step towards better understanding the basic mechanisms involved in IR-adaptive resistance in MEC cell lines and how to efficiently overcome this critical problem.
Laboratory of Epithelial Biology, Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI, USA.|Experimental Pathology Unit, Clinics Hospital of Porto Alegre, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.|Department of Oral Pathology, School of Dentistry, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.
Vivian P
VP
Wagner
Laboratory of Epithelial Biology, Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI, USA.|Experimental Pathology Unit, Clinics Hospital of Porto Alegre, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.
Marco A T
MA
Martins
Laboratory of Epithelial Biology, Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI, USA.|Experimental Pathology Unit, Clinics Hospital of Porto Alegre, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.|Department of Oral Pathology, School of Dentistry, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.
Manoela D
MD
Martins
Department of Restorative Sciences, University of Michigan School of Dentistry, Ann Arbor, MI, USA.
Kristy A
KA
Warner
Laboratory of Epithelial Biology, Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI, USA.|Experimental Pathology Unit, Clinics Hospital of Porto Alegre, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.|Department of Oral Pathology, School of Dentistry, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.
Liana P
LP
Webber
Laboratory of Epithelial Biology, Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI, USA.|Comprehensive Cancer Center, University of Michigan Ann Arbor, MI, USA.
Cristiane H
CH
Squarize
Department of Restorative Sciences, University of Michigan School of Dentistry, Ann Arbor, MI, USA.|Comprehensive Cancer Center, University of Michigan Ann Arbor, MI, USA.|Department of Otolaryngology, Medical School, University of Michigan, Ann Arbor, MI, USA.|Department of Biomedical Engineering, University of Michigan College of Engineering, Ann Arbor, MI, USA.
Jacques E
JE
Nör
Laboratory of Epithelial Biology, Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI, USA.|Comprehensive Cancer Center, University of Michigan Ann Arbor, MI, USA.
Rogerio M
RM
Castilho
D017209:Apoptosis; D015415:Biomarkers; D018277:Carcinoma, Mucoepidermoid / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival; D015870:Gene Expression; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000528:radiation effects; D011836:Radiation Tolerance / Q000235:genetics / Q000528:radiation effects; D011839:Radiation, Ionizing; D015398:Signal Transduction / Q000528:radiation effects
D015415:Biomarkers; D016328:NF-kappa B; D051550:I-kappa B Kinase
IKKα; cancer stem cells; irradiation; radio-adaptive; salivary cancer
Oncol Rep. 2014 Jan;31(1):456-62
24213797
Oncotarget. 2015 Sep 29;6(29):26633-50
26449187
Oral Oncol. 2013 Nov;49(11):1059-66
24035723
Int J Radiat Oncol Biol Phys. 1989 Feb;16(2):513-8
2921157
Br J Cancer. 1999 May;80(3-4):546-55
10408865
Gynecol Oncol. 2001 Jun;81(3):341-7
11371120
Prostate. 1999 Apr 1;39(1):8-15
10221260
Eur J Pharm Biopharm. 2014 Sep;88(1):186-93
24747809
Clin Cancer Res. 2005 Oct 15;11(20):7334-43
16243805
Cancer Lett. 2001 Oct 22;172(1):93-8
11595134
Chem Biol. 2007 Dec;14 (12 ):1386-92
18096507
Tumour Biol. 2010 Aug;31(4):363-72
20490962
Crit Rev Oncol Hematol. 2010 May;74(2):134-48
19939701
Nature. 2006 May 25;441(7092):431-6
16724054
J Urol. 2014 Feb;191(2):502-9
24045224
Mol Cell Biol. 1999 May;19(5):3485-95
10207072
Nat Rev Cancer. 2005 Jul;5(7):516-25
15965493
J Craniofac Surg. 2014 May;25(3):e289-91
24777018
Br Med J. 1918 Jan 26;1(2978):116-8
20768912
Cancer. 2005 Sep 15;104(6):1129-37
16080176
Oral Oncol. 2008 Apr;44(4):407-17
17825603
Clin Cancer Res. 2003 Dec 15;9(17):6316-25
14695130
J Clin Oncol. 2006 Feb 10;24(5):748-54
16401681
Nat Rev Drug Discov. 2012 Jun 29;11(7):505-6
22743966
FEBS Open Bio. 2013 Dec 30;4:96-104
24490130
Cancer. 1971 Apr;27(4):835-41
4929936
Cancer Biol Ther. 2009 May;8(9):765-73
19276662
Oncogene. 1998 Jun 25;16(25):3269-77
9681825
Mol Cancer Ther. 2004 Aug;3(8):985-92
15299081
Cancer Biol Ther. 2008 Apr;7(4):569-76
18305409
Recent Results Cancer Res. 2000;155:15-27
10693235
Eur J Cancer. 1981 May;17(5):539-48
7297593
Nat Rev Clin Oncol. 2015 Dec;12(12):732-42
26483297
Oncogene. 1995 Nov 16;11(10):2021-8
7478521
Planta Med. 2007 Oct;73(13):1389-96
17912675
J Clin Invest. 1991 Aug;88(2):691-5
1864978
Int J Radiat Oncol Biol Phys. 2014 Mar 1;88(3):677-85
24411622
Drug Discov Today. 2016 Jan;21(1):190-9
26456577
Immunol Res. 2008;42(1-3):3-18
18626576
Cancer Res. 2006 Sep 1;66(17):8352-5
16951142
Radiat Res. 1990 Sep;123(3):325-30
2145606
Mol Cell Biol. 2003 Apr;23 (7):2362-78
12640121
Cancer. 1973 May;31(5):1170-5
4705155
Planta Med. 2006 Oct;72(12):1121-6
16783693
Oral Surg Oral Med Oral Pathol Oral Radiol. 2012 Aug;114(2):230-9
22769409
Oncotarget. 2015 Oct 27;6(33):34494-509
26460734
Nat Rev Cancer. 2008 Jul;8(7):545-54
18511937
Int J Radiat Oncol Biol Phys. 2013 Jul 15;86(4):785-90
23664323
Dig Liver Dis. 2012 Jul;44(7):617-22
22440241
Radiother Oncol. 2007 Jun;83(3):304-10
17517444
PLoS One. 2014 Jan 22;9(1):e86329
24466029
Mol Cancer. 2013 Aug 02;12:86
23915189
Int J Cancer. 2001 Mar 20;95(2):128-34
11241324
Crit Rev Oncol Hematol. 2014 Aug;91(2):142-58
24636481
Free Radic Biol Med. 2008 Jan 1;44(1):1-13
17967430
Science. 1996 Nov 1;274(5288):784-7
8864119
Clin Cancer Res. 1996 Sep;2(9):1571-5
9816335
Int J Oncol. 2000 Dec;17(6):1231-5
11078810
Carcinogenesis. 2005 Aug;26(8):1395-403
15802300
Radiat Res. 2001 Apr;155(4):543-53
11260656
Nature. 2009 Apr 9;458(7239):780-3
19194462
Int J Oncol. 2015 Jan;46(1):389-94
25310746
Oncogene. 2014 Mar 6;33(10):1297-305
23474754
Head Neck. 2004 Aug;26(8):681-92; discussion 692-3
15287035
Int J Radiat Oncol Biol Phys. 2001 May 1;50(1):183-93
11316563
Cancer Chemother Rep. 1973 Nov-Dec;57(4):423-8
4586950
PLoS One. 2011 Apr 07;6(4):e18447
21490922
Cold Spring Harb Perspect Biol. 2010 Mar;2(3):a000158
20300203
Nat Rev Cancer. 2003 Feb;3(2):117-29
12563311
Biochem Pharmacol. 2010 May 1;79(9):1272-80
20067776
Int J Cancer. 2005 May 1;114(5):806-16
15609302
Cancer Res. 2010 Dec 15;70(24):10464-73
21159656
Head Neck Surg. 1986 Jan-Feb;8(3):177-84
3744850
Nat Commun. 2016 Feb 02;7:10438
26832959
Nat Rev Cancer. 2011 Apr;11(4):239-53
21430696
Biochim Biophys Acta. 2010 Apr;1805(2):167-80
20079806
Virchows Arch. 2005 May;446(5):475-82
15856292