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

Authors

  • Masahiro Yamamoto,

    Corresponding author
    1. Kampo Pharmacology Department, Tsumura Central Research Laboratories, Tsumura and Co., Ami, Ibaraki, Japan
    • Kampo Pharmacology Department, Tsumura Central Research Laboratories, Tsumura and Co., 3586 Yoshiwara, Ami-machi, Inashiki-gun, Ibaraki 300-11, Japan. Fax: 81-298-89-3867.
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  • Kazunori Fukuda,

    1. Cancer Prevention Division, National Cancer Center Research Institute, Tokyo, Japan
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  • Naoko Miura,

    1. Kampo Pharmacology Department, Tsumura Central Research Laboratories, Tsumura and Co., Ami, Ibaraki, Japan
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  • Rie Suzuki,

    1. Kampo Pharmacology Department, Tsumura Central Research Laboratories, Tsumura and Co., Ami, Ibaraki, Japan
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  • Toshitaka Kido,

    1. Kampo Pharmacology Department, Tsumura Central Research Laboratories, Tsumura and Co., Ami, Ibaraki, Japan
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  • Yasuhiro Komatsu

    1. Kampo Pharmacology Department, Tsumura Central Research Laboratories, Tsumura and Co., Ami, Ibaraki, Japan
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Abstract

The authors previously reported that transforming growth factor β1 (TGF-β1) 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-β1 –induced apoptosis in both. Analysis of analogous hormones in TGF-β1 –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-β1 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-β1 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-β1. Bcl-2 and Bcl-xS proteins were not detected, and Bax and Bad content did not change by treatment with TGF-β1 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-β1–induced apoptosis in the hepatoma cell lines.

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