Modulation of stress genes expression profile by nitric oxide-releasing aspirin in Jurkat T leukemia cells.

Abstract

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.

• Authors: Niharika Nath, Mitali Chattopadhyay, Ravinder Kodela, Song Tian, Peter Vlismas, Daniel Boring, James A Crowell, Khosrow Kashfi
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 79 Issue 12 Pg. 1759-71 (Jun 15 2010) ISSN: 1873-2968 [Electronic] England
• PMID: 20188076 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2010 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• HSP70 Heat-Shock Proteins
• HSPA1A protein, human
• Neoplasm Proteins
• nitroxy-butyl-acetylsalicylic acid
• Aspirin

Topics

• Antineoplastic Agents (chemistry, pharmacology)
• Aspirin (analogs & derivatives, chemistry, pharmacology)
• Dose-Response Relationship, Drug
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic (drug effects)
• Gene Silencing
• HSP70 Heat-Shock Proteins (genetics, metabolism)
• Humans
• Jurkat Cells
• Leukemia, T-Cell (drug therapy)
• Molecular Structure
• Neoplasm Proteins (genetics, metabolism)
• RNA Interference