Effects of estradiol and progesterone on tumor necrosis factor alpha-induced apoptosis in human hepatoma HuH-7 cells.
Oxidative stress, including the generation of reactive oxygen species (ROS), is known to be involved in apoptosis. Preventing apoptosis may thereby induce a malignant transformation of liver tumor cells. Estradiol (E2) is a potent endogenous antioxidant. We examined the proapoptotic role of progesterone as well as the antiapoptotic role of E2 in human hepatoma HuH-7 cells in a state of early apoptosis induced by tumor necrosis factor (TNF) alpha. The TNF alpha-induced ROS generation, lipid peroxidation, antioxidant enzyme consumption, a proapoptotic predominant expression of Bcl-2 family proteins, and a disruption of mitochondrial membrane potential were all inhibited by E2, and then they were further stimulated by progesterone in HuH-7 cells. The inhibitory effects of E2 were blocked by coincubation with progesterone. Treatment with the progesterone receptor antagonist RU486 led to the blockage of the progesterone-mediated responses to E2 pretreatment in TNF alpha-induced apoptosis. These findings demonstrate that E2 inhibits the TNF alpha-induced early apoptosis in hepatoma cells, by suppressing the oxidative stress processes, whereas progesterone acts in a manner opposite from the effects of E2, and the inhibitory effects of E2 were blocked by progesterone, thus leading to the apoptosis of hepatoma cells.
Cheng
Xinliang
X
Department of Digestive and Cardiovascular Medicine, Tokushima University Graduate School of Medicine, Kuramoto-cho, Tokushima 770-8503, Japan.
Shimizu
Ichiro
I
Yuan
Ying
Y
Wei
Mei
M
Shen
Mi
M
Huang
Huiwei
H
Urata
Mari
M
Sannomiya
Katsutaka
K
Fukuno
Hiroshi
H
Hashimoto-Tamaoki
Tomoko
T
Ito
Susumu
S
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D004347:Drug Interactions; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000096:biosynthesis; D047629:Estrogen Receptor beta / Q000096:biosynthesis; D005979:Glutathione Peroxidase / Q000378:metabolism; D006801:Humans; D007425:Intracellular Membranes / Q000187:drug effects; D015227:Lipid Peroxidation / Q000187:drug effects; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects; D011374:Progesterone / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D017382:Reactive Oxygen Species / Q000378:metabolism; D011980:Receptors, Progesterone / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000494:pharmacology; D013482:Superoxide Dismutase / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D000911:Antibodies, Monoclonal; D000975:Antioxidants; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D011980:Receptors, Progesterone; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D011374:Progesterone; D004958:Estradiol; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase