Budesonide exerts its chemopreventive efficacy during mouse lung tumorigenesis by modulating gene expressions.
Budesonide, a glucocorticoid, was proven to be a highly effective agent in preventing the development of lung tumors in A/J mice. In a lung tumor bioassay, budesonide produced 70% inhibition of tumor multiplicity and 94% reduction of total tumor load compared to benzopyrene (B[a]P) treated mice. Gene expression array analysis was performed on mouse lung tumors from this bioassay using Affymetrix U74Av2 GeneChips to determine gene expression changes associated with budesonide treatment. We found 363 genes that were changed between lung tumors induced by treatment with B[a]P and similar tumors treated with budesonide. Among them, 243 genes were overexpressed and 120 genes were underexpressed after budesonide treatment. In addition, 108 genes differentially expressed during mouse lung tumorigenesis (50 genes overexpressed and 58 genes underexpressed) were modulated back to normal levels after budesonide treatment when compared with the controls group. These genes are involved in a broad range of different pathways including control of cell cycle, signal transduction, and apoptosis and may play a role in the observed preventive effect. Our results suggest that budesonide exerts its effects of chemoprevention through growth arrest via Mad2/3 and through apoptosis via Bim/Blk and, by inference, caspase-8/9. Using the pathway visualization tool GenMapp, G protein pathway and MAPK cascade were also regulated by budesonide. Thus, we have determined, for the first time, the expression profiles of genes modulated by budesonide during murine lung tumorigenesis. Our results indicate that the chemopreventive effects of budesonide in the mouse lung tumorigenesis assay involved increase and decrease expression of a wide variety of genes in multiple signaling pathways.
Yao
Ruisheng
R
Department of Surgery and The Alvin J Siteman Cancer Center, Washington University School of Medicine, 660 S Euclid Avenue, St Louis, MO 63110, USA.
Wang
Yian
Y
Lemon
William J
WJ
Lubet
Ronald A
RA
You
Ming
M
D000818:Animals; D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D019819:Budesonide / Q000627:therapeutic use*; D018797:Cell Cycle Proteins / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D008175:Lung Neoplasms / Q000235:genetics* / Q000517:prevention & control*; D051379:Mice; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics
D016588:Anticarcinogenic Agents; D018797:Cell Cycle Proteins; D014157:Transcription Factors; D019819:Budesonide