Acidosis affects tumor cell survival through modulation of nitric oxide release.
The influence of environmental pH on the production of tumoricidal free radical nitric oxide (NO) was investigated in mouse fibrosarcoma L929 and rat glioma C6 cell lines. A combination of IFN-gamma and IL-1 induced a significant NO release and subsequent reduction of cell viability in tumor cell lines. Acidification of cell culture medium reduced tumor cell NO production in a pH-dependent manner. While the inhibitory effect of acidosis on NO production in C6 cells was associated with a further decrease in cell viability, it completely rescued L929 cells from NO-dependent apoptotic and necrotic death. Acidic pH diminished IFN-gamma+ IL-1-induced expression of inducible NO synthase (iNOS) mRNA and protein, and abolished the activation of iNOS transcription factor IRF-1 in L929 cells. Moreover, extracellular acidosis significantly impaired cytokine-induced phosphorylation of MAP kinase p44/42 (ERK1/2) and subsequent expression of transcription factor c-Fos in L929 cells. Finally, mild acidosis (pH 6.8) augmented, while severe acidosis (pH 6.0) reduced, IFN-gamma-induced iNOS activation/NO release and NO-dependent anticancer activity of rat and mouse macrophages. Taken together, our findings indicate that modulation of macrophage and tumor cell iNOS by an acidic microenvironment might influence the progression of NO-sensitive solid tumors.
Harhaji
Ljubica
L
Department of Neurobiology and Immunology, Institute for Biological Research, Belgrade, Serbia and Montenegro.
Popadic
Dusan
D
Miljkovic
Djordje
D
Cvetkovic
Ivana
I
Isakovic
Aleksandra
A
Trajkovic
Vladimir
V
D000138:Acidosis / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D005354:Fibrosarcoma / Q000188:drug therapy / Q000378:metabolism*; D005609:Free Radicals / Q000378:metabolism; D005910:Glioma / Q000188:drug therapy / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D050856:Interferon Regulatory Factor-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis*; D052247:Nitric Oxide Synthase Type II / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics; D051381:Rats; D014407:Tumor Cells, Cultured
D005609:Free Radicals; D050856:Interferon Regulatory Factor-1; D007375:Interleukin-1; C494258:Irf1 protein, mouse; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D009569:Nitric Oxide; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3