Molecular determinants of tumor response to hyperthermia
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE77310 | GEO | 2016/12/31
SECONDARY ACCESSION(S): PRJNA310007
REPOSITORIES: GEO
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Project description:Proteomic data from ovarian cancer cells (A2780 and SKOV3); treated cells with or without hyperthermia (46 deg C for 1 hr); 2 biological replicates for each cell line/condition
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Project description:The role of hyperthermic intraperitoneal chemotherapy (HIPEC) in epithelial ovarian cancer (EOC) is still controversial partly because of the poorly understood mechanism of action. Further an understanding of the underlying mechanisms could identify potential combination therapies. Here, we conduct a comprehensive multi-omics study (transcriptiome, proteome, and phosphoproteome) upon hyperthermia (HT) in ovarian cancer cells. Unbiased trans-omics approach deciphered a unique hyperthermia- induced molecular panorama and demonstrated rapid alterations in protein phosphorylation as the primary cell response upon HT. Based on the phospho-signature, we identified CDK kinases to be hyperactivated and responsible for the global signaling landscape upon HT. Molecular and functional experiments demonstrated the dynamic and reversible CDK activity, subsequent replication arrest, and early mitotic entry after HT. A follow-up drug screen identified WEE1 inhibition to synergistically kills cancer cells with HT. An in-house developed miniaturized devise delivered proof-of-concept that the combination of hyperthermia with WEE1i leads to dramatic anti-tumor responses in vivo. These findings provide new insights into how to improve the effectiveness of HIPEC in EOC.
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Project description:The rationale underlying hyperthermia is the fact that temperatures over 42.5˚C are highly cytotoxic to tumor cells. On the other hand, although mild hyperthermia at a range from 39 to 41˚C alone did not induce cytotoxicity in tumor cells, mild hyperthermia is reported to show a synergism with radiotherapy and anti-cancer drugs. Here, the effects of mild hyperthermia (41˚C for 30 min) on the gene expression in human lymphoma U937 cells were investigated using by an Affymetrix GeneChip system. Although the cells treated with the mild hyperthermia did not induce apoptosis, a significant increase in protein levels of heat shock proteins, Hsp40 and Hsp70, was observed following activation of heat shock factor-1. At 3 h post-treatment, 938 probe sets that were differentially expressed by >1.5-fold were identified. Keywords: mild hyperthermia, gene expression, Human lymphoma U937 cell
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Project description:Modulated electro-hyperthermia (mEHT) is a selective cancer treatment used in human oncology complementing other therapies. During mEHT, a focused electromagnetic field (EMF) is generated within the tumor, by elevated oxidative glycolysis (Warburg effect) and conductivity of the tumor. The EMF induce cell death by thermal and non-thermal effects. Here we investigated an aggressive, therapy resistant triple negative breast cancer (TNBC) model. 4T1/4T07 isografts inoculated orthotopically into female BALB/c mice were treated with mEHT 3-5 times. mEHT induced the upregulation of the stress related Hsp70 and cleaved caspase-3 proteins, resulting in effective inhibition of tumor growth and proliferation.
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Project description:Hyperthermia has shown unique advantages in tumor treatment as an anti-cancer treatment method, which combined with radiotherapy and/or chemotherapy reduces the side effects. However, its specific mechanism is unknown.
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Project description:To determine the signaling networks that are dysregulated in platinum-resistant ovarian cancer, gene expression data were obtained from, and compared between, the ovarian cancer cell line, A2780, and its cisplatin-resistant derivative, A2780cis. Gene expression data from a cisplatin-sensitive ovarian cancer cell line (A2780) were collected and compared to gene expression data from a cisplatin-resistant cell line (A2780cis). 6 independent experiments were completed for both the sensitive and resistant cell lines.
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Project description:Neural tube defects (NTDs) are one of the most common human birth defects, with a prevalence of approximately 1 in 1000 live births in the United States. In animal studies, deletion of p53 and hyperthermia leads to a significant increase in embryos that exhibit exencephaly. To evaluate the effects of hyperthermia on p53-deficient mouse embryos we used microarray approach to find genes modified by deletion of p53 and hyperthermia treatment in day 8.5 mouse embryos to identify genes that may be involved in the mechanisms underlining NTDs and begin to define the developmental role of p53 in the etiology of NTDs.
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Project description:Physical factors can have major influences on the proliferation and differentiation fate of hematopoietic stem cells in culture. Recently, we demonstrated that cord blood CD34+ cells undergo accelerated and increased megakaryocyte differentiation when incubated at 39°C. In this study, we investigated in detail the impacts of mild hyperthermia on the kinetics of megakaryocyte differentiation, maturation, polyploidization and cell viability. The qualitative and quantitative effects on Mk differentiation were found to be rapidly induced, and optimization of the culture length at 39°C led to greater Mk yields. Mild hyperthermia did not promote endomitosis of cord blood-derived Mk, but rather led to a small reduction in the proportion of polyploid Mk. Moreover, it had little impact on viability but induced a significant shift in the proportion of cells undergoing apoptosis at 37°C to necrosis at 39°C. Finally, our results suggest that the effects on megakaryocyte differentiation could be the consequences of aberrant expression of key megakaryocyte transcription factors induced by mild hyperthermia. Keywords: Effect of mild hyperthermia on Mk differentiation
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Project description:Hyperthermia is widely used to treat patients with various cancers. Here, the effects of heat stress at 41°C for 30 min (mild hyperthermia) on the gene expression in OUMS-36 human normal fibroblast cells were investigated using an Affymetrix GeneChip system. The cells were treated with mild hyperthermia, followed by incubation for 0, 1, or 3 h at 37°C. No cell death was observed in the mild hyperthermia-treated cells. On the other hand, many genes that were differentially expressed by a factor 1.5 or greater were identified in the cells treated with the mild hyperthermia.
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Project description:Hyperthermia is widely used to treat patients with various cancers. Here, the effects of heat stress at 41°C for 30 min (mild hyperthermia) on the gene expression in Hs68 human skin normal fibroblast cells were investigated using an Affymetrix GeneChip system. The cells were treated with mild hyperthermia, followed by incubation for 0, 1, or 3 h at 37°C. No cell death was observed in the mild hyperthermia-treated cells. On the other hand, many genes that were differentially expressed by a factor 1.5 or greater were identified in the cells treated with the mild hyperthermia.
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