Abrogating HSP response augments cell death induced by As2O3 in glioma cell lines.
OBJECTIVE
We previously reported that Arsenic trioxide (ATO) can inhibit glioma growth both in vitro and in vivo. While the use of ATO alone for solid tumor treatment sometimes was found to be ineffective which may be due to the protective pathways including heat shock proteins (HSPs) response induced by ATO. In this study, we modified HSPs expression to investigate whether HSPs had some effect on ATO induced glioma cell death.


METHODS
Trypan bule exclusion assay, mitochondrial membrane potential (MMP) Assay, and SubG1 detection were used to evaluate cell viability and western-blot was employed to detect HSPs and some apoptosis markers expression induced by ATO. Heat pre-treatment, HSPs inhibitor, or Heat Shock factor-1 (HSF1) knockdown by SiRNA was employed to modify HSPs levels.


RESULTS
It was showed that KNK437 (HSPs inhibitor) or HSF1 knockdown significantly enhanced cell death, MMP disruption, JNK phosphorylation and caspase-3 cleavage induced by ATO, which was accompanied by abrogation of HSPs induction, while heat pre-treatment with clear HSPs induction had strong protection on the effects mentioned above.


CONCLUSIONS
Those data suggested that HSPs play protective roles on ATO induced cell death in glioma. Inhibition of HSPs may have a synergistic effect with ATO on glioma treatment.
Song
Xueming
X
Department of Neurosurgery, 1st Affiliated Hospital of Harbin Medical University, Nangang District, Harbin, P.R. China.
Chen
Zhiqiang
Z
Wu
Chunbo
C
Zhao
Shiguang
S
D000970:Antineoplastic Agents / Q000494:pharmacology*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D001559:Benzhydryl Compounds / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D005910:Glioma / Q000473:pathology*; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D018869:Heat-Shock Response / Q000187:drug effects / Q000502:physiology; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D010087:Oxides / Q000494:pharmacology*; D011760:Pyrrolidinones / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014343:Trypan Blue
D000970:Antineoplastic Agents; D001152:Arsenicals; D001559:Benzhydryl Compounds; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; C000619706:HSF1 protein, human; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins; C410027:KNK 437; D010087:Oxides; D011760:Pyrrolidinones; D034741:RNA, Small Interfering; D014157:Transcription Factors; D048670:MAP Kinase Kinase 4; D053148:Caspase 3; D014343:Trypan Blue; D000077237:Arsenic Trioxide