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1.
Toxicol In Vitro ; 42: 191-199, 2017 Aug.
Article in English | MEDLINE | ID: mdl-28473196

ABSTRACT

Palladium nanoparticles have been increasingly used in catalytic processes, wastewater treatment, electronics, and biomedicine. However, recent evidence proved that these nanoparticles are able to induce adverse effects both in in vitro and in vivo models. Nevertheless, molecular mechanisms underlying the toxic effects are still poorly understood. Therefore, this study aimed to investigate the potential toxicological mechanisms of palladium nanoparticles assessing their effects on normal diploid rat fibroblast and lung carcinoma human epithelial cell lines. Several endpoints such as cell growth, cell cycle progression, DNA damage, induction of apoptosis, reactive oxygen species production and expression of cell cycle regulatory proteins were evaluated. Results showed that palladium nanoparticles inhibited cell growth in a dose- and time-dependent manner in both cell lines, although with a more evident action on fibroblasts. Interestingly, inhibition of cell growth was not associated with the induction of apoptosis. Cell cycle progression was arrested in the G0/G1 phase and DNA damage was evident in both cell lines even if only a slight increase in the intracellular reactive oxygen species levels was detected. These findings provide valuable insight into understanding the molecular mechanisms responsible of palladium nanoparticles toxicity whose identification is essential to define an adequate risk assessment process.


Subject(s)
Epithelial Cells/drug effects , Fibroblasts/drug effects , Lung/cytology , Metal Nanoparticles/toxicity , Palladium/toxicity , A549 Cells , Animals , Apoptosis/drug effects , Cell Cycle/drug effects , Cell Cycle Proteins/metabolism , Cell Line , Cell Proliferation/drug effects , Cell Survival/drug effects , DNA Damage , Epithelial Cells/metabolism , Fibroblasts/metabolism , Humans , Rats , Reactive Oxygen Species/metabolism
2.
Int J Oncol ; 41(1): 235-41, 2012 Jul.
Article in English | MEDLINE | ID: mdl-22552444

ABSTRACT

PAX2 is a paired box transcription factor possessing a fundamental role in the embryogenesis of hindbrain and urinary tract. PAX genes are proto-oncogenes, PAX2 expression may contribute to the pathogenesis of renal cell carcinoma. Because of the expression of PAX2 in the developing hindbrain and its essential role in cerebellar development, it has been hypothesized that PAX2 may also be involved in medulloblastoma tumorigenesis. We investigated the expression pattern of PAX2 and various genes of the neuronal lineage in medulloblastoma and glioma cell lines. We found high expression of PAX2 mRNA and PAX2 protein in medulloblastoma cells and some glioma cell lines independent of their neuronal lineage gene expression signature. Gene suppression of PAX2 decreased the expression of the PAX2 transcriptional target GDNF in Daoy cells and had a profound cytotoxic effect in vitro on Daoy medulloblastoma and T98G glioma cells. Expression of PAX2 was then assessed in two separate medulloblastoma tissue microarrays with a total of 61 patient samples by immunohistochemistry. PAX2 expression was detected in the majority of medulloblastoma samples and correlated with less differentiated histology. Therefore, PAX2 is a biomarker for a more aggressive medulloblastoma phenotype and may represent a novel therapeutic target.


Subject(s)
Apoptosis Regulatory Proteins/genetics , Cerebellar Neoplasms/metabolism , Gene Expression Regulation, Neoplastic , Medulloblastoma/metabolism , PAX2 Transcription Factor/genetics , Animals , Antigens, Differentiation/genetics , Antigens, Differentiation/metabolism , Apoptosis Regulatory Proteins/metabolism , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Cell Line, Tumor , Cell Proliferation , Cerebellar Neoplasms/genetics , Cerebellar Neoplasms/pathology , Gene Expression Profiling , Gene Knockdown Techniques , Glial Cell Line-Derived Neurotrophic Factor/genetics , Glial Cell Line-Derived Neurotrophic Factor/metabolism , Homeodomain Proteins/genetics , Homeodomain Proteins/metabolism , Medulloblastoma/genetics , Medulloblastoma/pathology , Mice , PAX2 Transcription Factor/metabolism , PAX5 Transcription Factor/metabolism , PAX8 Transcription Factor , Paired Box Transcription Factors/metabolism , RNA Interference , Tissue Array Analysis
3.
Oncogene ; 31(33): 3764-76, 2012 Aug 16.
Article in English | MEDLINE | ID: mdl-22120717

ABSTRACT

P53 has an important role in the processing of starvation signals. P53-dependent molecular mediators of the Warburg effect reduce glucose consumption and promote mitochondrial function. We therefore hypothesized that the retention of wild-type p53 characteristic of primary glioblastomas limits metabolic demands induced by deregulated signal transduction in the presence of hypoxia and nutrient depletion. Here we report that short hairpin RNA-mediated gene suppression of wild-type p53 or ectopic expression of mutant temperature-sensitive dominant-negative p53(V135A) increased glucose consumption and lactate production, decreased oxygen consumption and enhanced hypoxia-induced cell death in p53 wild-type human glioblastoma cells. Similarly, genetic knockout of p53 in HCT116 colon carcinoma cells resulted in reduced respiration and hypersensitivity towards hypoxia-induced cell death. Further, wild-type p53 gene silencing reduced the expression of synthesis of cytochrome c oxidase 2 (SCO2), an effector necessary for respiratory chain function. An SCO2 transgene reverted the metabolic phenotype and restored resistance towards hypoxia in p53-depleted and p53 mutant glioma cells in a rotenone-sensitive manner, demonstrating that this effect was dependent on intact oxidative phosphorylation. Supplementation with methyl-pyruvate, a mitochondrial substrate, rescued p53 wild-type but not p53 mutant cells from hypoxic cell death, demonstrating a p53-mediated selective aptitude to metabolize mitochondrial substrates. Further, SCO2 gene silencing in p53 wild-type glioma cells sensitized these cells towards hypoxia. Finally, lentiviral gene suppression of SCO2 significantly enhanced tumor necrosis in a subcutaneous HCT116 xenograft tumor model, compatible with impaired energy metabolism in these cells. These findings demonstrate that glioma and colon cancer cells with p53 wild-type status can skew the Warburg effect and thereby reduce their vulnerability towards tumor hypoxia in an SCO2-dependent manner. Targeting SCO2 may therefore represent a valuable strategy to enhance sensitivity towards hypoxia and may complement strategies targeting glucose metabolism.


Subject(s)
Apoptosis , Carrier Proteins/physiology , Cell Respiration , Colonic Neoplasms/therapy , Glioma/therapy , Mitochondrial Proteins/physiology , Tumor Suppressor Protein p53/physiology , Base Sequence , Cell Hypoxia , Cell Line, Tumor , Colonic Neoplasms/metabolism , Colonic Neoplasms/pathology , Glioma/metabolism , Glioma/pathology , Glucose/metabolism , Humans , Molecular Chaperones , Molecular Sequence Data , Necrosis , Tumor Suppressor Protein p53/antagonists & inhibitors
4.
J Am Optom Assoc ; 47(3): 306, 1976 Mar.
Article in English | MEDLINE | ID: mdl-1027805
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