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Hepatocarcinogenic potential of the glucocorticoid antagonist RU486 in B6C3F1 mice: effect on apoptosis, expression of oncogenes and the tumor suppressor gene p53.

Youssef JA, Badr MZ - Mol. Cancer (2003)

Bottom Line: RU 486 also significantly increased hepatic expression of the oncogenes mdm2 and JunB, while reducing that of the tumor suppressor gene p53.This effect may be mediated through increases in the hepatic expression of the oncogene mdm2, coupled with decreases in that of the tumor suppressor gene p53.The decrease in hepatocellular proliferation caused by RU 486 may be related to effects other than its anti-glucocorticoid activity.

View Article: PubMed Central - HTML - PubMed

Affiliation: University of Missouri-Kansas City, 2411 Holmes Street, Kansas City, MO 64108, USA. badrm@umkc.edu

ABSTRACT

Background: Glucocorticoids inhibit hepatocellular proliferation and modulate the expression of oncogenes and tumor suppressor genes via mechanisms involving the glucocorticoid receptor. Glucocorticoids also produce a receptor-mediated inhibitory effect on both basal and hormone-stimulated expression of a newly discovered family of molecules important for shutting off cytokine action. We therefore hypothesized that inhibiting glucocorticoid receptors may disturb hepatocellular growth and apoptosis. Consequently, we investigated the effect of RU486, a potent antagonist of the glucocorticoid receptor, on basal levels of hepatocellular proliferation and apoptosis in male B6C3F1 mice. Furthermore, we evaluated the effect of this compound on cellular genes involved in the regulation of these important processes.

Results: Data show that treatment of male B6F3C1 mice with RU486 (2 mg/kg/d, ip) for 7 days dramatically inhibited liver cell proliferation by about 45% and programmed hepatocellular death by approximately 66%. RU 486 also significantly increased hepatic expression of the oncogenes mdm2 and JunB, while reducing that of the tumor suppressor gene p53.

Conclusion: Exposure to RU486 may ultimately enhance the susceptibility of the liver to cancer risk by diminishing its ability to purge itself of pre-cancerous cells via apoptosis. This effect may be mediated through increases in the hepatic expression of the oncogene mdm2, coupled with decreases in that of the tumor suppressor gene p53. The decrease in hepatocellular proliferation caused by RU 486 may be related to effects other than its anti-glucocorticoid activity.

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Hepatocellular proliferation (A) and apoptosis (B) in response to RU486. Mice were treated, and cell proliferation as well as apoptotic cells were quantified as described under Methods. Data are means ± SEM from 4–6 animals per group.
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Figure 1: Hepatocellular proliferation (A) and apoptosis (B) in response to RU486. Mice were treated, and cell proliferation as well as apoptotic cells were quantified as described under Methods. Data are means ± SEM from 4–6 animals per group.

Mentions: In control mice, 1.55 ± 0.12% of hepatocytes were labeled with BrDU (Fig. 1A). Treatment with RU 486 significantly diminished these labeling indices by approximately 45% to 0.86 ± 0.039% (Fig 1A). Similarly, RU 486 caused a remarkable decrease in programmed cell death in the liver. In control animals, 2.68 ± 0.7% of hepatocytes were undergoing apoptosis (Fig 1B). These levels were significantly reduced by 66% to 0.9 ± 0.16% in livers of mice pretreated with RU 486 (Fig 1B).


Hepatocarcinogenic potential of the glucocorticoid antagonist RU486 in B6C3F1 mice: effect on apoptosis, expression of oncogenes and the tumor suppressor gene p53.

Youssef JA, Badr MZ - Mol. Cancer (2003)

Hepatocellular proliferation (A) and apoptosis (B) in response to RU486. Mice were treated, and cell proliferation as well as apoptotic cells were quantified as described under Methods. Data are means ± SEM from 4–6 animals per group.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC149417&req=5

Figure 1: Hepatocellular proliferation (A) and apoptosis (B) in response to RU486. Mice were treated, and cell proliferation as well as apoptotic cells were quantified as described under Methods. Data are means ± SEM from 4–6 animals per group.
Mentions: In control mice, 1.55 ± 0.12% of hepatocytes were labeled with BrDU (Fig. 1A). Treatment with RU 486 significantly diminished these labeling indices by approximately 45% to 0.86 ± 0.039% (Fig 1A). Similarly, RU 486 caused a remarkable decrease in programmed cell death in the liver. In control animals, 2.68 ± 0.7% of hepatocytes were undergoing apoptosis (Fig 1B). These levels were significantly reduced by 66% to 0.9 ± 0.16% in livers of mice pretreated with RU 486 (Fig 1B).

Bottom Line: RU 486 also significantly increased hepatic expression of the oncogenes mdm2 and JunB, while reducing that of the tumor suppressor gene p53.This effect may be mediated through increases in the hepatic expression of the oncogene mdm2, coupled with decreases in that of the tumor suppressor gene p53.The decrease in hepatocellular proliferation caused by RU 486 may be related to effects other than its anti-glucocorticoid activity.

View Article: PubMed Central - HTML - PubMed

Affiliation: University of Missouri-Kansas City, 2411 Holmes Street, Kansas City, MO 64108, USA. badrm@umkc.edu

ABSTRACT

Background: Glucocorticoids inhibit hepatocellular proliferation and modulate the expression of oncogenes and tumor suppressor genes via mechanisms involving the glucocorticoid receptor. Glucocorticoids also produce a receptor-mediated inhibitory effect on both basal and hormone-stimulated expression of a newly discovered family of molecules important for shutting off cytokine action. We therefore hypothesized that inhibiting glucocorticoid receptors may disturb hepatocellular growth and apoptosis. Consequently, we investigated the effect of RU486, a potent antagonist of the glucocorticoid receptor, on basal levels of hepatocellular proliferation and apoptosis in male B6C3F1 mice. Furthermore, we evaluated the effect of this compound on cellular genes involved in the regulation of these important processes.

Results: Data show that treatment of male B6F3C1 mice with RU486 (2 mg/kg/d, ip) for 7 days dramatically inhibited liver cell proliferation by about 45% and programmed hepatocellular death by approximately 66%. RU 486 also significantly increased hepatic expression of the oncogenes mdm2 and JunB, while reducing that of the tumor suppressor gene p53.

Conclusion: Exposure to RU486 may ultimately enhance the susceptibility of the liver to cancer risk by diminishing its ability to purge itself of pre-cancerous cells via apoptosis. This effect may be mediated through increases in the hepatic expression of the oncogene mdm2, coupled with decreases in that of the tumor suppressor gene p53. The decrease in hepatocellular proliferation caused by RU 486 may be related to effects other than its anti-glucocorticoid activity.

Show MeSH
Related in: MedlinePlus