Modulation of stress genes expression profile by nitric oxide-releasing aspirin in Jurkat T leukemia cells
Department of Life Sciences, New York Institute of Technology, New York, NY 10023, USA. Biochemical pharmacology
(Impact Factor: 5.01).
02/2010; 79(12):1759-71. DOI: 10.1016/j.bcp.2010.02.011
NO-donating aspirin (NO-ASA, para isomer) has been reported to exhibit strong growth inhibitory effect in Jurkat T-acute lymphoblastic leukemia (T-ALL) cells mediated in part by beta-catenin degradation and caspase activation, but the mechanism(s) still remains unclear. In this study, DNA oligoarrays with 263 genes were used to examine the gene expression profiles relating to stress and drug metabolism, and characterize the stress responses at IC(50) and subIC(50) concentrations of p-NO-ASA (20 and 10microM, respectively) in Jurkat T cells. A total of 22 genes related to heat shock response, apoptosis signaling, detoxifiers and Phase II enzymes, and regulators of cell growth were altered in expression by array analysis based on the expression fold change criteria of > or =1.5-fold or < or =0.65-fold. Real time quantitative RT-PCR confirmed that 20microM p-NO-ASA strongly upregulated the mRNA levels of two heat shock genes HSPA1A (41.5+/-7.01-fold) and HSPA6 (100.4+/-8.11-fold), and FOS (16.2+/-3.2-fold), moderately upregulated HSPH1 (1.71+/-0.43-fold), FMO4 (4.5+/-1.67-fold), CASP9 (1.77+/-0.03-fold), DDIT3 (5.6+/-0.51-fold), and downregulated NF-kappaB1 (0.54+/-0.01-fold) and CCND1 (0.69+/-0.06-fold). Protein levels of Hsp70, the product of HSPA1A, and fos were increased in p-NO-ASA-treated Jurkat T and HT-29 colon cancer cells in a dose-dependent manner. Silencing of Hsp70 enhanced the growth inhibitory effect of p-NO-ASA at low concentrations. The altered gene expression patterns by NO-ASA in Jurkat T cells suggest mechanisms for carcinogen metabolism, anti-proliferative activity and possible chemoprotective activity in T-ALL.
Available from: Pei-Gen Xiao
[Show abstract] [Hide abstract]
ABSTRACT: Flavin-containing monooxygenase (FMO), like cytochrome P450 (CYP), is a monooxygenase that uses the reducing equivalents of
NADPH to reduce one atom of molecular oxygen to water, while the other atom is used to oxidize the substrate. Recently, it
was shown that some CYP isoforms have been subject to positive selection. However, it is unknown whether the highly conserved
phase I detoxification enzyme, FMO, has undergone similar positive Darwinian selection. We used maximum-likelihood models
of codon substitution, evolutionary fingerprinting, and cross species comparison to investigate the occurrence of adaptive
evolution in FMO sequences. We used recent genomic data from a range of species, including vertebrates and invertebrates.
We present the evidence for the occurrence of adaptive evolution in mammalian FMO 3, 4, 5, and fugu FMOs but not in mammalian
FMO 1, FMO 2, frog FMOs, other fish FMOs and invertebrate FMOs. The sites under adaptive evolution were significantly associated
with the insertion domain in mammalian FMO 5. We identified specific amino acid sites in FMOs 3–5 that are likely targets
for selection based on the patterns of parallel amino acid change. The most likely role of adaptive evolution is the repair
of mutations that permitted optimal NADP+ binding and improved catalytic efficiency. The occurrence of positive selection during the evolution of phase I detoxification
enzymes such as FMOs 3–5 and fugu FMO suggests the occurrence of both high selection pressure acting on species within their
unique habitats and significant changes in intensity and direction (forms of xenobiotics and drugs) resulting from changes
in microhabitat and food.
Keywordsflavin-containing monooxygenase–adaptive evolution–positive selection–insertion domain–evolutionary fingerprint–maximum likelihood
Available from: Diana V Maltseva
[Show abstract] [Hide abstract]
ABSTRACT: High and moderate intensity endurance exercise alters gene expression in human white blood cells (WBCs), but the understanding of how this effect occurs is limited. To increase our knowledge of the nature of this process, we investigated the effects of passing the anaerobic threshold (AnT) on the gene expression profile in WBCs of athletes. Nineteen highly trained skiers participated in a treadmill test with an incremental step protocol until exhaustion (ramp test to exhaustion, RTE). The average total time to exhaustion was 14:40 min and time after AnT was 4:50 min. Two weeks later, seven of these skiers participated in a moderate treadmill test (MT) at 80% peak O(2) uptake for 30 min, which was slightly below their AnTs. Blood samples were obtained before and immediately after both tests. RTE was associated with substantially greater leukocytosis and acidosis than MT. Gene expression in WBCs was measured using whole genome microarray expression analysis before and immediately after each test. A total of 310 upregulated genes were found after RTE, and 69 genes after MT of which 64 were identical to RTE. Both tests influenced a variety of known gene pathways related to inflammation, stress response, signal transduction and apoptosis. A large group of differentially expressed previously unknown small nucleolar RNA and small Cajal body RNA was found. In conclusion, a 15-min test to exhaustion was associated with substantially greater changes of gene expression than a 30-min test just below the AnT.
Available from: Khosrow Kashfi
[Show abstract] [Hide abstract]
ABSTRACT: Nitric oxide (NO) is one of the 10 smallest molecules found in nature. It is a simple gaseous free radical whose predominant functions is that of a messenger through cGMP. In mammals, NO is synthesized by the enzyme nitric oxide synthase (NOS) of which there are three isoforms. Neuronal (nNOS, NOS1) and endothelial (eNOS, NOS3) are constitutive calcium-dependent forms of the enzyme that regulate neural and vascular function respectively. The third isoform (iNOS, NOS2), is calcium-independent and is inducible. In many tumors, iNOS expression is high, however, the role of iNOS during tumor development is very complex and quite perplexing, with both promoting and inhibiting actions having been described. This review will aim to summarize the dual actions of iNOS-derived NO showing that the microenvironment of the tumor is a contributing factor to these observations and ultimately to cellular outcomes.
Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.
Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.