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Histone deacetylase inhibition decreases proliferation and potentiates the effect of ionizing radiation in atypical teratoid/rhabdoid tumor cells

ABSTRACT: Atypical teratoid/rhabdoid tumor (ATRT) is a highly malignant CNS neoplasm whichprimarily occurs in children under three years of age. Due to poor outcomes with intense and toxicmultimodality treatment, new therapies are urgently needed. Histone deacetylase inhibitors (HDIs)have been evaluated as novel agents for multiple malignancies and have been shown to function asradiosensitizers. They act as epigenetic modifiers and lead to re-expression of inappropriatelyrepressed genes, proteins, and cellular functions. Due to the underlying chromatin remodeling genemutation in ATRT, HDIs are ideal candidates for therapeutic evaluation. To evaluate the role of HDIsagainst ATRT in vitro, we assessed the effect of drug treatment on proliferation, apoptosis, and geneexpression. Additionally, we examined HDI pretreatment as a radiosensitization strategy for ATRT.MTS and clonogenic assays demonstrated that HDI treatment significantly reduces the proliferativecapacity of BT-12 and BT-16 ATRT cells. Also, the HDI SNDX-275 was able to induce apoptosis in bothcell lines and induced p21Waf1/Cip1 protein expression as measured by Western blot. Evaluation ofdifferential gene expression by microarray and pathway analysis after HDI treatment demonstratedalterations of several key ATRT cellular functions. Finally, we showed that HDI pretreatmenteffectively potentiates the effect of ionizing radiation on ATRT cells as measured by clonogenic assay.These findings suggest that the addition of HDIs to ATRT therapy may prove beneficial, especiallywhen administered in combination with current treatment modalities such as radiation. Keywords: ATRT; HDAC inhibitor; radiosensitization

ORGANISM(S): Homo sapiens

PROVIDER: GSE31122 | GEO | 2011/11/14

SECONDARY ACCESSION(S): PRJNA144957

REPOSITORIES: GEO

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Project description:Atypical teratoid/rhabdoid tumor (ATRT) is a highly malignant CNS neoplasm whichprimarily occurs in children under three years of age. Due to poor outcomes with intense and toxicmultimodality treatment, new therapies are urgently needed. Histone deacetylase inhibitors (HDIs)have been evaluated as novel agents for multiple malignancies and have been shown to function asradiosensitizers. They act as epigenetic modifiers and lead to re-expression of inappropriatelyrepressed genes, proteins, and cellular functions. Due to the underlying chromatin remodeling genemutation in ATRT, HDIs are ideal candidates for therapeutic evaluation. To evaluate the role of HDIsagainst ATRT in vitro, we assessed the effect of drug treatment on proliferation, apoptosis, and geneexpression. Additionally, we examined HDI pretreatment as a radiosensitization strategy for ATRT.MTS and clonogenic assays demonstrated that HDI treatment significantly reduces the proliferativecapacity of BT-12 and BT-16 ATRT cells. Also, the HDI SNDX-275 was able to induce apoptosis in bothcell lines and induced p21Waf1/Cip1 protein expression as measured by Western blot. Evaluation ofdifferential gene expression by microarray and pathway analysis after HDI treatment demonstratedalterations of several key ATRT cellular functions. Finally, we showed that HDI pretreatmenteffectively potentiates the effect of ionizing radiation on ATRT cells as measured by clonogenic assay.These findings suggest that the addition of HDIs to ATRT therapy may prove beneficial, especiallywhen administered in combination with current treatment modalities such as radiation. Keywords: ATRT; HDAC inhibitor; radiosensitization BT12 and BT16 cells were plated and subsequently treated for 24hr with IC25 concentrations of SNDX-275 (Sigma), at which time total RNA was collected. IC25 concentrations were calculated based on MTS assay.For BT12, the SNDX-275 IC25 was 1.4uM. For BT16, it was 0.44uM. The controls had DMSO added at equivalent volumes.

Project description:Background: We previously demonstrated that B16F1 melanoma tumors growing in syngeneic germline-deleted TNFR1,2 -/- mice were more sensitive to ionizing radiation (IR) compared to tumors growing in C57BL/6 wild-type mice; however, the mechanisms linked to this difference in radiosensitivity are not fully understood. Methodology/ Principal Findings: We used DNA microarrays to identify alterations in the expression of functional gene clusters associated with the radiosensitization of B16F1 tumors growing in TNFR1,2 -/- mice. At the basal level, disruption of host stromal TNFα signaling resulted in the over-expression of tumor genes involved in extracellular matrix remodeling and angiogenesis. Phenotypically, these tumors exhibited a reduced vascular density, which induced the expression of oxidative stress signaling pathways and increased levels of tissue hypoxia and necrosis. These alterations were paralleled by the suppression of genes involved in chromosomal stability and key effectors of the ATM-dependent/ non-homologous end-joining pathways including phosphorylated-ATM, BRCA1, and RAD51, which resulted in greater DNA double-strand breaks and caspase 3 activation following IR treatment. Conclusions/ Significance: Taken together, these results demonstrate that disruption of TNFα signaling in the host stroma mediates transcriptional and phenotypic changes in tumors which may alter tumor radiosensitivity. These results suggest a critical role for TNFα in the maintenance of tumor-associated vasculature and radioresistance. They also indicate that TNFα signaling blockade in stromal cells may represent a strategy for tumor radiosensitization. To investigate the genes associated with the radiosensitization of B16F1 melanoma tumors in the context of disrupted stromal TNFα signaling, we performed expression profiling of B16F1 tumors grown in syngeneic TNFR 1, 2 -/- and wild-type C57BL/6 mice. Tumors were lysed to collect total RNA, pooled by treatment group according to total RNA level, and analyzed in duplicates with Affymetrix GeneChip® Mouse Genome 430 2.0 Arrays.

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Histone deacetylase inhibition decreases proliferation and potentiates the effect of ionizing radiation in atypical teratoid/rhabdoid tumor cells

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