Inhibition by dexamethasone of transforming growth factor beta1-induced apoptosis in rat hepatoma cells: a possible association with Bcl-xL induction.
The authors previously reported that transforming growth factor beta1 (TGF-beta1) induces apoptosis in McA-RH7777 (7777) and McA-RH8994 (8994) rat hepatoma cell lines. Although these cell lines exhibit different responses to glucocorticoid treatment in various cellular functions and gene expression, dexamethasone (DEX) inhibited spontaneous and TGF-beta1-induced apoptosis in both. Analysis of analogous hormones in TGF-beta1-induced apoptosis in 8994 cells suggested the inhibitory effect to be glucocorticoid-specific. By cell-cycle analysis and DNA fragmentation assay using sodium butyrate, a G1-arrest-inducing reagent, regulation of apoptosis by TGF-beta1 and DEX was shown independent of the cell cycle. For elucidation of the mechanisms of anti-apoptotic action of DEX, the effects of various chemical probes on this apoptosis model were examined, and various reagents known to exhibit anti-apoptotic activity in other experimental systems were found to be ineffective. The effect of TGF-beta1 and DEX on cellular amounts of several apoptosis-related proteins, members of the Bcl-2 family, Bcl-2, Bcl-xL, Bcl-xS, Bad, and Bax was also examined. DEX drastically increased Bcl-xL in both cell lines irrespective of the presence of TGF-beta1. Bcl-2 and Bcl-xS proteins were not detected, and Bax and Bad content did not change by treatment with TGF-beta1 or DEX. Progesterone (Prog), a partial antagonist for glucocorticoid receptor, inhibited the effects of DEX on apoptosis and Bcl-xL expression in 8994 cells. Thus, Bcl-xL induction by DEX would appear closely associated with its inhibitory effect on spontaneous and TGF-beta1-induced apoptosis in the hepatoma cell lines.
Yamamoto
M
M
Kampo Pharmacology Department, Tsumura and Co., Ami, Ibaraki, Japan.
Fukuda
K
K
Miura
N
N
Suzuki
R
R
Kido
T
T
Komatsu
Y
Y
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology*; D008114:Liver Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis*; D051381:Rats; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D051020:bcl-X Protein
C494813:Bcl2l1 protein, rat; D019253:Proto-Oncogene Proteins c-bcl-2; D016212:Transforming Growth Factor beta; D051020:bcl-X Protein; D003907:Dexamethasone