Inhibition by dexamethasone of transforming growth factor β1,-induced apoptosis in rat hepatoma cells: A possible association with Bcl-xL induction

Abstract

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.

Interferon α-induced apoptosis on rat preneoplastic liver is mediated by hepatocytic transforming growth factor β1

“…These reductions were explained by a greater programmed cell death in the foci than in surrounding hepatocytes. Because the changes of pro-and antiapoptotic proteins induced by IFN-␣2b were similar to those attributed to TGF-␤ 1 , 14,15,19 we studied the possibility that TGF-␤ 1 could be involved in the programmed cell death induced by IFN-␣2b. Thus, the present work determines for the first time that endogenous TGF-␤ 1 is implicated in the increased apoptosis on the foci of IFN␣2b-treated rats.…”

“…11 However, the involvement of Bcl-2, Bax, and Bcl-x L proteins in TGF-␤ 1 -induced apoptosis has not been completely established. TGF-␤ 1 decreased the antiapoptotic protein Bcl-x L in diverse hepatoma cell lines, 14,15 whereas in other hepatoma cells no changes in Bax or Bcl-x L were observed. 18 On the other hand, overexpression of Bcl-2 blocked induction of apoptosis by TGF-␤ 1 in human hepatoma cells.…”

Dexamethasone inhibits spontaneous apoptosis in primary cultures of human and rat hepatocytes via Bcl-2 and Bcl-xL induction

“…14 ± 16 Although glucocorticoids induce rapid apoptosis in susceptible thymocyte and lymphocyte populations, several studies have demonstrated the inhibitory effects of glucocorticoids against apoptosis in various models: (i) DEX inhibits spontaneous as well as TNF-a-induced human neutrophil apoptosis, 17 ± 19 (ii) DEX and hydrocortisone abolish tumour necrosis factor a (TNFa)-induced cytoxicity of several tumour cell lines via inhibition of phospholipase A 2 activity, 20,21 and (iii) DEX inhibits spontaneous apoptosis and transforming growth factor b 1 -induced apoptosis in rat hepatoma cells via Bcl-xL induction. 22,23 However, there appears to be a dual role of glucocorticoids in the regulation of cell death although the mechanism of the anti-apoptotic effects of glucocorticoids has rarely been investigated.…”

Dexamethasone protects primary cultured hepatocytes from death receptor-mediated apoptosis by upregulation of cFLIP

“…5 Furthermore, DEX has been shown to either inhibit apoptosis in some cells such as human neutrophils, 6 tumor cells, 7 and primary human and rat hepatocytes 8 or induce apoptosis in others including thymocytes and lymphocytes. 9,10 The antiapoptotic effect by DEX is regulated by several sets of genes, the best characterized of which are the Bcl-2 family such as Bcl-2 and Bcl-xL, which prevent spontaneous apoptosis of cultured primary hepatocytes.…”