Delineation of an antiapoptotic action of glucocorticoids in hepatoma cells: the role of nuclear factor-kappaB.
Glucocorticoids are primarily recognized for their profound anti-inflammatory actions and their ability to induce lymphocyte apoptosis. We report here that, in contrast to their effect on cells of the immune system, glucocorticoids suppress serum deprivation induced apoptosis of rat hepatoma (HTC) cells. Suppression of apoptosis in these cells occurs at physiological concentrations of glucocorticoid and is abrogated by the glucocorticoid antagonist RU486. Although HTC cells also express receptors for progesterone, estrogen, and thyroid hormone, ligands for these receptors fail to rescue these cells from programmed cell death. Because the sensitivity of cells to apoptotic stimuli is often regulated by the ratio of antiapoptotic to proapoptotic Bcl-2 family members, we analyzed the influence of glucocorticoids and induction of apoptosis by serum starvation on the expression of these proteins. Bcl-2, Bcl-xL, Bad, Bak, and Bax levels were not altered by either treatment. Mitochondrial function has recently been implicated as a critical early regulator of apoptosis in many cells including hepatocytes. Dexamethasone treatment blocked a decrease in this potential (delta psi(m)) during serum deprivation induced apoptosis in HTC cells, indicating an action of this hormone upstream of mitochondria. We also show that the induction of apoptosis in HTC cells is associated with a decrease in nuclear factor (NF)-kappaB. Treatment with dexamethasone effectively blocked the loss of nuclear NF-kappaB, suggesting that this hormone acts to suppress apoptosis of HTC cells via regulation of this nuclear transcription factor. This hypothesis was confirmed by transfection experiments that show that expression of a superrepressor of NF-kappaB inhibits the ability of dexamethasone to rescue HTC cells from apoptosis induced by serum deprivation.
Evans-Storms
R B
RB
Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
Cidlowski
J A
JA
D000818:Animals; D017209:Apoptosis; D002455:Cell Division; D002470:Cell Survival; D005938:Glucocorticoids / Q000502:physiology*; D008114:Liver Neoplasms, Experimental / Q000503:physiopathology; D016328:NF-kappa B / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D014407:Tumor Cells, Cultured
D005938:Glucocorticoids; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2