Abstract
Objective. Cervical carcinoma tumors containing radioresistant cells are associated with decreased local control and survival. Therefore, strategies to increase cell kill during radiotherapy have a clear rationale. It was previously determined that treatment with the corticosteroid dexamethasone increased radioresistance and decreased apoptosis in C4-1 cervical carcinoma cells. The goal of this study was to determine whether hormone antagonists, specifically Mifepristone (RU486), could reverse the effects of dexamethasone on clonogenic survival and apoptosis following γ-irradiation. Methods. Cervical carcinoma cell line C4-1 cells were exposed to 1 μM dexamethasone in the presence or absence of 1 μM Mifepristone (RU486), a hormone antagonist, and irradiation. Cells were analyzed for steroid-dependent HPV E6/E7 mRNA expression (by Northern blot analysis), clonogenic survival, and apoptosis (by Annexin V staining and the DNA fragmentation assay). In addition, p53 protein levels were determined by Western blot analysis. Results. The hormone antagonist RU486 reversed dexamethasone-dependent upregulation of E6/E7 mRNA and restored radiation-induced p53 expression, apoptosis, and clonogenic survival to levels similar to those observed following irradiation alone. Conclusion. RU486 reverses glucocorticoid- dependent upregulation of HPV E6/E7, which corresponds to restoration of p53 expression, and restores radiosensitivity and apoptosis following γ- irradiation. Therefore, it appears that along with radiation, RU486 may be a beneficial agent in the treatment of hormone-reactive cervical tumors. (C) 2000 Academic Press.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 177-182 |
| Number of pages | 6 |
| Journal | Gynecologic Oncology |
| Volume | 77 |
| Issue number | 1 |
| DOIs | |
| State | Published - Apr 2000 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Obstetrics and Gynecology
- Oncology
Cite this
RU486 increases radiosensitivity and restores apoptosis through modulation of HPV E6/E7 in dexamethasone-treated cervical carcinoma cells. / Kamradt, Merideth C.; Mohideen, Najeeb; Vaughan, Andrew T M.
In: Gynecologic Oncology, Vol. 77, No. 1, 04.2000, p. 177-182.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - RU486 increases radiosensitivity and restores apoptosis through modulation of HPV E6/E7 in dexamethasone-treated cervical carcinoma cells
AU - Kamradt, Merideth C.
AU - Mohideen, Najeeb
AU - Vaughan, Andrew T M
PY - 2000/4
Y1 - 2000/4
N2 - Objective. Cervical carcinoma tumors containing radioresistant cells are associated with decreased local control and survival. Therefore, strategies to increase cell kill during radiotherapy have a clear rationale. It was previously determined that treatment with the corticosteroid dexamethasone increased radioresistance and decreased apoptosis in C4-1 cervical carcinoma cells. The goal of this study was to determine whether hormone antagonists, specifically Mifepristone (RU486), could reverse the effects of dexamethasone on clonogenic survival and apoptosis following γ-irradiation. Methods. Cervical carcinoma cell line C4-1 cells were exposed to 1 μM dexamethasone in the presence or absence of 1 μM Mifepristone (RU486), a hormone antagonist, and irradiation. Cells were analyzed for steroid-dependent HPV E6/E7 mRNA expression (by Northern blot analysis), clonogenic survival, and apoptosis (by Annexin V staining and the DNA fragmentation assay). In addition, p53 protein levels were determined by Western blot analysis. Results. The hormone antagonist RU486 reversed dexamethasone-dependent upregulation of E6/E7 mRNA and restored radiation-induced p53 expression, apoptosis, and clonogenic survival to levels similar to those observed following irradiation alone. Conclusion. RU486 reverses glucocorticoid- dependent upregulation of HPV E6/E7, which corresponds to restoration of p53 expression, and restores radiosensitivity and apoptosis following γ- irradiation. Therefore, it appears that along with radiation, RU486 may be a beneficial agent in the treatment of hormone-reactive cervical tumors. (C) 2000 Academic Press.
AB - Objective. Cervical carcinoma tumors containing radioresistant cells are associated with decreased local control and survival. Therefore, strategies to increase cell kill during radiotherapy have a clear rationale. It was previously determined that treatment with the corticosteroid dexamethasone increased radioresistance and decreased apoptosis in C4-1 cervical carcinoma cells. The goal of this study was to determine whether hormone antagonists, specifically Mifepristone (RU486), could reverse the effects of dexamethasone on clonogenic survival and apoptosis following γ-irradiation. Methods. Cervical carcinoma cell line C4-1 cells were exposed to 1 μM dexamethasone in the presence or absence of 1 μM Mifepristone (RU486), a hormone antagonist, and irradiation. Cells were analyzed for steroid-dependent HPV E6/E7 mRNA expression (by Northern blot analysis), clonogenic survival, and apoptosis (by Annexin V staining and the DNA fragmentation assay). In addition, p53 protein levels were determined by Western blot analysis. Results. The hormone antagonist RU486 reversed dexamethasone-dependent upregulation of E6/E7 mRNA and restored radiation-induced p53 expression, apoptosis, and clonogenic survival to levels similar to those observed following irradiation alone. Conclusion. RU486 reverses glucocorticoid- dependent upregulation of HPV E6/E7, which corresponds to restoration of p53 expression, and restores radiosensitivity and apoptosis following γ- irradiation. Therefore, it appears that along with radiation, RU486 may be a beneficial agent in the treatment of hormone-reactive cervical tumors. (C) 2000 Academic Press.
UR - http://www.scopus.com/inward/record.url?scp=0034005997&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0034005997&partnerID=8YFLogxK
U2 - 10.1006/gyno.1999.5724
DO - 10.1006/gyno.1999.5724
M3 - Article
C2 - 10739708
AN - SCOPUS:0034005997
VL - 77
SP - 177
EP - 182
JO - Gynecologic Oncology
JF - Gynecologic Oncology
SN - 0090-8258
IS - 1
ER -