Abrogating HSP Response Augments Cell Death Induced by As2O3 in Glioma Cell Lines

Abstract

504Malignant gliomas are the most common and lethal tumors of the central nervous system and are resistant to many kinds of treatment, including radiation, chemotherapy, and other adjuvant therapies 1,2 . Although considerable progress has been made in the treatment of glioma, its prognosis is still very poor 3 . The inefficacy of these therapeutic modalities in curing gliomas is due to the resistance of glioma cells and the difficulty of achieving complete tumor resection. There is therefore an urgent need to devise alternative therapeutic strategies to combat gliomas.We previously reported that Arsenic Trioxide (As2O3, or ATO) can inhibit glioma growth both in vitro and in vivo [4][5][6] , which demonstrated the potent therapeutic effects of this drug. ABSTRACT: Objectives: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. Conclusion: 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. RÉSUMÉ: La suppression de la réponse HSP augmente la mort cellulaire induite par As203 dans les lignées cellulaires de gliomes. Objectifs :Nous avons rapporté antérieurement que le trioxyde d'arsenic (TOA) peut inhiber la croissance de gliomes tant in vitro qu'in vivo. Cependant, l'utilisation du TOA seul pour le traitement de tumeurs solides s'avérait parfois inefficace, ce qui pourrait être dû aux voies protectrices telles la réponse aux protéines de choc thermique (HSP) induite par le TOA. Dans cette étude, nous avons modifié l'expression des HSP pour déterminer si les HSP avaient un effet sur la mort de cellules de gliomes induite par le TOA. Méthodes : Le test d'exclusion au bleu trypan, le test de potentiel membranaire mitochondrial (PMM) et la détection de cellules en phase Sub-G1 ont été utilisés pour évaluer la viabilité cellulaire, et le buvardage de western pour détecter les HSP et l'expression de certains marqueurs de l'apoptose induits par le TOA. No...

Characterizing the Altered Cellular Proteome Induced by the Stress-Independent Activation of Heat Shock Factor 1

“…42−44 FKBP·cHSF1 activation afforded a small but significant increase in cellular viability when HEK293T-Rex cells are challenged with heat (Figure 6A) or As(III) (Figure 6B), consistent with the capacity of stress-independent HSF1 activation to protect cells against stress.…”

Conditioned Media from Human Adipose Tissue-Derived Mesenchymal Stem Cells and Umbilical Cord-Derived Mesenchymal Stem Cells Efficiently Induced the Apoptosis and Differentiation in Human Glioma Cell Lines In Vitro

“…Differentiation agents for malignant gliomas remain a real challenge. Some studies have shown arsenic trioxide (As 2 O 3 ) and forskolin can also trigger apoptosis and differentiation in glioma cells [39, 40]. In our study, we unexpectedly found a very strong differentiation effect of conditioned MSCs medium.…”

The roles of mitoferrin-2 in the process of arsenic trioxide-induced cell damage in human gliomas

“…Human glioma treatment is especially challenging because current treatments, such as chemical therapy, drastically affect patient quality of life. As 2 O 3 has been successfully used for gliomas in a number of clinical trials and experiments because of its significant anticancer property [ 1 , 2 ]. In previous researches, As 2 O 3 (3 to 10 μM) could also induce apoptosis in cultured bone marrow mesenchymal stem cells [ 26 , 27 ].…”

“…Chemotherapy and/or radiotherapy are the main approaches for glioma treatment after surgery. As 2 O 3 as an antitumor agent has shown efficacy in treating glioma in laboratory tests [ 1 , 2 ]. Additionally, As 2 O 3 has potential as a mitochondrial toxin that can induce reactive oxygen species (ROS) production; these mainly originate in the intracellular mitochondrial respiratory chain and further toxic byproducts subsequently produced could lead to mitochondrial damage [ 3 ].…”