Valproic acid-induced amphiregulin secretion confers resistance to temozolomide treatment in human glioma cells.
Amphiregulin
/ genetics
Antibodies, Blocking
/ pharmacology
Antineoplastic Agents, Alkylating
/ pharmacology
Biomarkers, Tumor
Brain Neoplasms
/ drug therapy
Cell Line, Tumor
Drug Resistance, Neoplasm
/ genetics
Drug Synergism
Gene Knockdown Techniques
Glioblastoma
/ drug therapy
Humans
Lentivirus
/ genetics
Neuroglia
/ drug effects
Temozolomide
/ pharmacology
Valproic Acid
/ pharmacology
Journal
BMC cancer
ISSN: 1471-2407
Titre abrégé: BMC Cancer
Pays: England
ID NLM: 100967800
Informations de publication
Date de publication:
01 Aug 2019
01 Aug 2019
Historique:
received:
14
01
2019
accepted:
16
06
2019
entrez:
3
8
2019
pubmed:
3
8
2019
medline:
18
2
2020
Statut:
epublish
Résumé
Glioblastoma multiforme (GBM) is the most severe type of primary brain tumor with a high mortality rate. Although extensive treatments for GBM, including resection, irradiation, chemotherapy and immunotherapy, have been tried, the prognosis is still poor. Temozolomide (TMZ), an alkylating agent, is a front-line chemotherapeutic drug for the clinical treatment of GBM; however, its effects are very limited because of the chemoresistance. Valproic acid (VPA), an antiepileptic agent with histone deacetylase inhibitor activity, has been shown to have synergistic effects with TMZ against GBM. The mechanism of action of VPA on TMZ combination therapy is still unclear. Accumulating evidence has shown that secreted proteins are responsible for the cross talking among cells in the tumor microenvironment, which may play a critical role in the regulation of drug responses. To understand the effect of VPA on secreted proteins in GBM cells, we first used the antibody array to analyze the cell culture supernatant from VPA-treated and untreated GBM cells. The results were further confirmed by lentivirus-mediated knockdown and exogenous recombinant administration. Our results showed that amphiregulin (AR) was highly secreted in VPA-treated cells. Knockdown of AR can sensitize GBM cells to TMZ. Furthermore, pretreatment of exogenous recombinant AR significantly increased EGFR activation and conferred resistance to TMZ. To further verify the effect of AR on TMZ resistance, cells pre-treated with AR neutralizing antibody markedly increased sensitivity to TMZ. In addition, we also observed that the expression of AR was positively correlated with the resistance of TMZ in different GBM cell lines. The present study aimed to identify the secreted proteins that contribute to the modulation of drug response. Understanding the full set of secreted proteins present in glial cells might help reveal potential therapeutic opportunities. The results indicated that AR may potentially serve as biomarker and therapeutic approach for chemotherapy regimens in GBM.
Sections du résumé
BACKGROUND
BACKGROUND
Glioblastoma multiforme (GBM) is the most severe type of primary brain tumor with a high mortality rate. Although extensive treatments for GBM, including resection, irradiation, chemotherapy and immunotherapy, have been tried, the prognosis is still poor. Temozolomide (TMZ), an alkylating agent, is a front-line chemotherapeutic drug for the clinical treatment of GBM; however, its effects are very limited because of the chemoresistance. Valproic acid (VPA), an antiepileptic agent with histone deacetylase inhibitor activity, has been shown to have synergistic effects with TMZ against GBM. The mechanism of action of VPA on TMZ combination therapy is still unclear. Accumulating evidence has shown that secreted proteins are responsible for the cross talking among cells in the tumor microenvironment, which may play a critical role in the regulation of drug responses.
METHODS
METHODS
To understand the effect of VPA on secreted proteins in GBM cells, we first used the antibody array to analyze the cell culture supernatant from VPA-treated and untreated GBM cells. The results were further confirmed by lentivirus-mediated knockdown and exogenous recombinant administration.
RESULTS
RESULTS
Our results showed that amphiregulin (AR) was highly secreted in VPA-treated cells. Knockdown of AR can sensitize GBM cells to TMZ. Furthermore, pretreatment of exogenous recombinant AR significantly increased EGFR activation and conferred resistance to TMZ. To further verify the effect of AR on TMZ resistance, cells pre-treated with AR neutralizing antibody markedly increased sensitivity to TMZ. In addition, we also observed that the expression of AR was positively correlated with the resistance of TMZ in different GBM cell lines.
CONCLUSIONS
CONCLUSIONS
The present study aimed to identify the secreted proteins that contribute to the modulation of drug response. Understanding the full set of secreted proteins present in glial cells might help reveal potential therapeutic opportunities. The results indicated that AR may potentially serve as biomarker and therapeutic approach for chemotherapy regimens in GBM.
Identifiants
pubmed: 31370819
doi: 10.1186/s12885-019-5843-6
pii: 10.1186/s12885-019-5843-6
pmc: PMC6670223
doi:
Substances chimiques
Amphiregulin
0
Antibodies, Blocking
0
Antineoplastic Agents, Alkylating
0
Biomarkers, Tumor
0
Valproic Acid
614OI1Z5WI
Temozolomide
YF1K15M17Y
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
756Subventions
Organisme : Chang Gung Medical Research Council
ID : CMRPG6C0041, CMRPG6C0042, and CMRPG6C0043
Organisme : Ministry of Science and Technology
ID : 105-2320-B-415-001
Références
Am J Transl Res. 2017 Jun 15;9(6):3138-3147
pubmed: 28670399
J Exp Clin Cancer Res. 2016 Feb 02;35:23
pubmed: 26830677
Eur J Clin Pharmacol. 2017 Mar;73(3):357-363
pubmed: 27889835
EMBO J. 2001 Dec 17;20(24):6969-78
pubmed: 11742974
Mol Neurobiol. 2007 Oct;36(2):137-51
pubmed: 17952658
Clin Cancer Res. 2008 Apr 15;14(8):2351-6
pubmed: 18413824
Biochim Biophys Acta. 2013 Nov;1834(11):2418-28
pubmed: 23269363
Biochim Biophys Acta Gen Subj. 2018 Mar;1862(3):557-566
pubmed: 29203282
Curr Opin Neurobiol. 2017 Dec;47:156-161
pubmed: 29096244
N Engl J Med. 2013 Sep 5;369(10):985-6
pubmed: 24004141
J Neurooncol. 2012 Mar;107(1):61-7
pubmed: 22037799
Crit Rev Clin Lab Sci. 2016;53(2):121-31
pubmed: 26479834
Nature. 2012 Jul 26;487(7408):500-4
pubmed: 22763439
Oncol Rep. 2019 Jun;41(6):3413-3423
pubmed: 30942446
Am J Cancer Res. 2015 Feb 15;5(3):945-55
pubmed: 26045979
J Mammary Gland Biol Neoplasia. 2008 Jun;13(2):159-69
pubmed: 18398673
J Clin Invest. 2012 Jan;122(1):253-66
pubmed: 22156195
Int J Cancer. 2019 Apr 1;144(7):1735-1745
pubmed: 30289977
Recent Pat Anticancer Drug Discov. 2015;10(2):145-62
pubmed: 25782916
Cancer Res. 2005 Oct 15;65(20):9176-84
pubmed: 16230376
Cancer Lett. 2007 Aug 28;254(1):30-41
pubmed: 17321672
Cancer Sci. 2010 Nov;101(11):2351-60
pubmed: 20726858
J Cancer. 2019 Feb 23;10(6):1479-1488
pubmed: 31031857
Int J Cancer. 2009 Apr 15;124(8):1990-6
pubmed: 19123474
Neuropathol Appl Neurobiol. 2018 Feb;44(2):139-150
pubmed: 28815663
Semin Cell Dev Biol. 2014 Apr;28:31-41
pubmed: 24463227
BMC Cancer. 2012 Mar 13;12:88
pubmed: 22409860
Int J Mol Sci. 2017 May 12;18(5):
pubmed: 28498322
Acta Neuropathol. 2007 Aug;114(2):97-109
pubmed: 17618441
Int J Oncol. 2002 Nov;21(5):941-8
pubmed: 12370739
Biochim Biophys Acta. 2013 Nov;1834(11):2233-41
pubmed: 23542208
Mol Cell Proteomics. 2016 Feb;15(2):355-61
pubmed: 26342039
Lancet Oncol. 2009 May;10(5):459-66
pubmed: 19269895
Apoptosis. 2018 Dec;23(11-12):563-575
pubmed: 30171377
Cancer Res. 2004 Feb 1;64(3):1079-86
pubmed: 14871841
Cell Oncol (Dordr). 2017 Apr;40(2):167-180
pubmed: 28160167
Cancer Res. 1994 Aug 1;54(15):3959-62
pubmed: 8033121
Pharmacol Ther. 2018 Apr;184:13-41
pubmed: 29080702
Cell Death Dis. 2013 Oct 24;4:e876
pubmed: 24157870
Biochem Biophys Res Commun. 2008 Feb 1;366(1):110-6
pubmed: 18053801
Adv Exp Med Biol. 2013;986:171-87
pubmed: 22879069
Biochem Pharmacol. 2004 Sep 15;68(6):989-96
pubmed: 15313392
Glia. 2009 Oct;57(13):1374-85
pubmed: 19229996
J Biomed Biotechnol. 2012;2012:987495
pubmed: 22701311
J Mol Med (Berl). 2011 Mar;89(3):303-15
pubmed: 21340685
CNS Drugs. 2002;16(10):669-94
pubmed: 12269861
Curr Opin Oncol. 2001 Jan;13(1):70-7
pubmed: 11148690
N Engl J Med. 2014 Feb 20;370(8):699-708
pubmed: 24552317
Neuro Oncol. 2014 Jul;16(7):896-913
pubmed: 24842956
Oral Oncol. 2006 Apr;42(4):381-90
pubmed: 16376136
Mol Cancer Ther. 2017 Dec;16(12):2689-2700
pubmed: 28802253
Cancer Res. 2008 Apr 1;68(7):2259-65
pubmed: 18381432
Cell Death Dis. 2018 Aug 6;9(8):841
pubmed: 30082680
J Neurochem. 2012 Jul;122(2):444-55
pubmed: 22564186
Endocrinology. 2004 Dec;145(12):5493-503
pubmed: 15331576
J Biol Chem. 2010 Apr 2;285(14):10678-89
pubmed: 20145244
Cell Commun Signal. 2017 Oct 2;15(1):37
pubmed: 28969644
Nature. 2015 Apr 16;520(7547):368-72
pubmed: 25807485
Biochem Biophys Res Commun. 2004 Apr 9;316(3):693-7
pubmed: 15033455
Oncotarget. 2015 Oct 27;6(33):35004-22
pubmed: 26413814
Neurol Med Chir (Tokyo). 2012;52(4):186-93
pubmed: 22522328
Int J Oncol. 2015 Dec;47(6):2073-81
pubmed: 26497673
J Neurooncol. 2015 Apr;122(2):263-71
pubmed: 25648357
J Immunol. 2011 Aug 15;187(4):1733-44
pubmed: 21742971
Cancer Biol Ther. 2012 Apr;13(6):389-400
pubmed: 22313638
Int J Mol Med. 2016 Jun;37(6):1686-96
pubmed: 27082972
Nature. 2012 Jul 26;487(7408):505-9
pubmed: 22763448
J Clin Neurosci. 2017 Jan;35:13-23
pubmed: 27771233
Hum Mol Genet. 2004 Dec 15;13(24):3029-43
pubmed: 15496427
J Biol Chem. 2015 Sep 18;290(38):23401-15
pubmed: 26245897
Cell Commun Signal. 2013 Dec 20;11:97
pubmed: 24359404
Ups J Med Sci. 2012 May;117(2):99-112
pubmed: 22509804
J Biol Chem. 2006 Dec 8;281(49):37728-37
pubmed: 17035230
Br J Cancer. 2000 Sep;83(5):588-93
pubmed: 10944597
Int J Gynecol Cancer. 2011 Dec;21(9):1547-54
pubmed: 22080896
Oncotarget. 2016 May 17;7(20):28849-67
pubmed: 26700624
J Clin Oncol. 2010 Dec 20;28(36):5247-56
pubmed: 21079146
Clin Cancer Res. 2002 Aug;8(8):2725-34
pubmed: 12171906
N Engl J Med. 2005 Mar 10;352(10):987-96
pubmed: 15758009
Cancer Res. 2006 Jun 15;66(12):6129-38
pubmed: 16778186