TNFalpha induces chromosomal abnormalities independent of ROS through IKK, JNK, p38 and caspase pathways.
A role for pro-inflammatory cytokines in inflammation-related cancers has been suggested, but mechanisms are not defined. Here, we demonstrate that treatment of HeLa cells with TNFalpha increases chromosomal aberration. In contrast, IL-1beta did not increase, but rather decreased chromosomal aberration. TNFalpha and IL-1beta increased the production of H2O2 to similar levels in cells, suggesting that increased production of reactive oxygen species might not be the premier factor involved. Reducing H2O2 through overexpression of catalase or treatment of cells with NAC or BHA did not have an effect on TNF-induced chromosomal aberration. TNFalpha-induced NO production has been implicated in DNA damage. Inhibiting NO did not reduce TNF-induced chromosomal aberration. Inhibiting IKK, JNK, and p38 kinase as well as caspases decreased TNF-induced chromosomal aberration, and a correlation between TNF-induced apoptosis and CA generation was not found. Single-strand DNA breaks give rise to double-strand breaks, which then results in chromosomal breaks, when replication forks reach the single-strand breaks during S-phase. In cells progressing through S-phase, TNFalpha activation of IKK, JNK, and p38 is significantly reduced. However, these kinases were activated by IL-1beta in S-phase. The possibility that these pathways, in a TNF-specific manner, may regulate either the generation of single- and double-strand breaks or their repair, thereby resulting in increased chromosomal aberration, is discussed.
Higashimoto
Tomoyasu
T
Department of Molecular Microbiology and Immunology, USC/Norris Comprehensive Cancer Center, Keck School of Medicine at USC, Los Angeles, CA 90033, USA.
Panopoulos
Andreas
A
Hsieh
Chih-Lin
CL
Zandi
Ebrahim
E
D020169:Caspases / Q000378:metabolism*; D002869:Chromosome Aberrations; D004260:DNA Repair; D004277:DNA, Single-Stranded / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D007375:Interleukin-1 / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D017382:Reactive Oxygen Species; D016196:S Phase; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D004277:DNA, Single-Stranded; D007375:Interleukin-1; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D051550:I-kappa B Kinase; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020169:Caspases