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P53 and PI3K/AKT signalings are up-regulated in flies with defects in the THO complex.

ABSTRACT: The THO complex (THO) is an evolutionary conserved protein required for the formation of export-competent mRNP. The growing evidence indicates that the metazoan THO plays important roles in cell differentiation and cellular stress response. But the underlying mechanisms are poorly understood. Herein we examined the relevance of THO to cellular signaling pathways involved in cell differentiation and cellular stress response. When we examined the endogenous p53 level in the testis, it was sustained much longer during spermatogenesis in the THO mutant compared to that of wild-type. In flies with impaired THO, overexpression of p53 by eye-specific GAL4 not only enhanced p53-mediated retinal degeneration, but p53 level was also elevated compared to the control flies. Since the body size of the THO mutant flies was significantly larger than control flies, we also examined whether the PI3K/AKT signaling is enhanced in the mutant flies. The results showed that the endogenous level of phosphorylated AKT, which is the active form, was highly elevated in the THO mutants. Taken together our results suggested that both p53 and PI3K/AKT signalings are up-regulated in the flies with impaired THO.

SUBMITTER: Moon S

PROVIDER: S-EPMC3887910 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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p53 and PI3K/AKT signalings are up-regulated in flies with defects in the THO complex.

Moon Sungjin S Chung Yun Doo YD

Molecules and cells 20130308 3

The THO complex (THO) is an evolutionary conserved protein required for the formation of export-competent mRNP. The growing evidence indicates that the metazoan THO plays important roles in cell differentiation and cellular stress response. But the underlying mechanisms are poorly understood. Herein we examined the relevance of THO to cellular signaling pathways involved in cell differentiation and cellular stress response. When we examined the endogenous p53 level in the testis, it was sustaine ...[more]

PMID: 23475424

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Project description:BackgroundAcquired resistance of 5-fluorouracil (5-FU) remains a clinical challenge in colorectal cancer (CRC), and efforts to develop targeted agents to reduce resistance have not yielded success. Metabolic reprogramming is a key cancer hallmark and confers several tumor phenotypes including chemoresistance. Glucose metabolic reprogramming events of 5-FU resistance in CRC has not been evaluated, and whether abnormal glucose metabolism could impart 5-FU resistance in CRC is also poorly defined.MethodsThree separate acquired 5-FU resistance CRC cell line models were generated, and glucose metabolism was assessed by measuring glucose and lactate utilization, RNA and protein expressions of glucose metabolism-related enzymes and changes of intermediate metabolites of glucose metabolite pool. The protein levels of hypoxia inducible factor 1α (HIF-1α) in primary tumors and circulating tumor cells of CRC patients were detected by immunohistochemistry and immunofluorescence. Stable HIF1A knockdown in cell models was established with a lentiviral system. The influence of both HIF1A gene knockdown and pharmacological inhibition on 5-FU resistance in CRC was evaluated in cell models in vivo and in vitro.ResultsThe abnormality of glucose metabolism in 5-FU-resistant CRC were described in detail. The enhanced glycolysis and pentose phosphate pathway in CRC were associated with increased HIF-1α expression. HIF-1α-induced glucose metabolic reprogramming imparted 5-FU resistance in CRC. HIF-1α showed enhanced expression in 5-FU-resistant CRC cell lines and clinical specimens, and increased HIF-1α levels were associated with failure of fluorouracil analog-based chemotherapy in CRC patients and poor survival. Upregulation of HIF-1α in 5-FU-resistant CRC occurred through non-oxygen-dependent mechanisms of reactive oxygen species-mediated activation of PI3K/Akt signaling and aberrant activation of β-catenin in the nucleus. Both HIF-1α gene knock-down and pharmacological inhibition restored the sensitivity of CRC to 5-FU.ConclusionsHIF-1α is a potential biomarker for 5-FU-resistant CRC, and targeting HIF-1a in combination with 5-FU may represent an effective therapeutic strategy in 5-FU-resistant CRC.

Project description:BackgroundEffective removal of pathogenic bacteria is key to improving the prognosis of sepsis. Polymorphonuclear neutrophils (PMNs) are the most important components of innate cellular immunity and play vital roles in clearing pathogenic bacteria. However, the metabolic characteristics and immunomodulatory pathways of PMNs during sepsis have not been investigated. In the present study, we explored the immune metabolism characteristics of PMNs and the mechanism by which neutrophilic glycolysis is regulated during sepsis.MethodsMetabolomics analysis was performed on PMNs isolated from 14 septic patients, 26 patients with acute appendicitis, and 19 healthy volunteers. Transcriptome analysis was performed on the PMNs isolated from the healthy volunteers and the patients with sepsis to assess glycolysis and investigate its mechanism. Lipopolysaccharide (LPS) was used to stimulate the neutrophils isolated from the healthy volunteers at different time intervals to build an LPS-tolerant model. Chemotaxis, phagocytosis, lactate production, oxygen consumption rate (OCR), and extracellular acidification rate (ECAR) were evaluated.ResultsTranscriptomics showed significant changes in glycolysis and the mTOR/HIF-1α signaling pathway during sepsis. Metabolomics revealed that the Warburg effect was significantly altered in the patients with sepsis. We discovered that glycolysis regulated PMNs' chemotaxis and phagocytosis functions during sepsis. Lactate dehydrogenase A (LDHA) downregulation was a key factor in the inhibition of glycolysis in PMNs. This study confirmed that the PI3K/Akt-HIF-1α pathway was involved in the LDHA expression level and also influenced PMNs' chemotaxis and phagocytosis functions.ConclusionsThe inhibition of glycolysis contributed to neutrophil immunosuppression during sepsis and might be controlled by PI3K/Akt-HIF-1α pathway-mediated LDHA downregulation. Our study provides a scientific theoretical basis for the management and treatment of patients with sepsis and promotes to identify therapeutic target for the improvement of immune function in sepsis.

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P53 and PI3K/AKT signalings are up-regulated in flies with defects in the THO complex.

Publications

p53 and PI3K/AKT signalings are up-regulated in flies with defects in the THO complex.

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