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BMI1 silencing enhances docetaxel activity and impairs antioxidant response in prostate cancer

Crea, Francesco; Duhagon Serrat, Maria A.; Hurt, Elaine M.; Thomas, Suneetha B.; Danesi, Romano and Farrar, William L. (2011). BMI1 silencing enhances docetaxel activity and impairs antioxidant response in prostate cancer. International Journal of Cancer, 128(8) pp. 1946–1954.

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The BMI1 oncogene promotes prostate cancer (PC) progression. High B-cell-specific Moloney murine leukemia virus integration site 1 (BMI1) expression predicts poor prognosis in PC patients. Recent evidence suggests that BMI1 may also play a role in docetaxel chemoresistance. However, mechanisms and clinical significance of BMI1-related chemoresistance have not been investigated. For this purpose, BMI1 was silenced in 2 PC cell lines (LNCaP and DU 145). Cell proliferation and apoptosis after docetaxel treatment were measured. Guanine oxidation was assessed by in-cell western. Global gene expression analysis was performed on BMI1 silenced cells. Oncomine database was used to compare in vitro data with gene expression in PC samples. BMI1 silencing had no effect on cell proliferation but significantly enhanced docetaxel-induced antitumor activity. Gene expression analysis demonstrated that BMI1 silencing downregulates a set of antioxidant genes. Docetaxel treatment increased guanine oxidation, whereas the antioxidant N-acetyl cysteine rescued docetaxel-induced cell death. Examination of clinical datasets revealed a positive correlation of BMI1 and antioxidant gene expression. BMI1-controlled antioxidant genes were predictive of poor prognosis in PC patients. In conclusion, BMI1 enhances antioxidant response, thereby allowing PC survival after docetaxel-based chemotherapy. BMI1-controlled antioxidant genes are overexpressed in aggressive PC and should be tested as predictors of chemotherapy failure.

Item Type: Journal Item
Copyright Holders: 2010 UICC
ISSN: 1097-0215
Keywords: docetaxel; Polycomb; prostate
Academic Unit/School: Faculty of Science, Technology, Engineering and Mathematics (STEM) > Life, Health and Chemical Sciences
Faculty of Science, Technology, Engineering and Mathematics (STEM)
Item ID: 45841
Depositing User: Francesco Crea
Date Deposited: 18 Apr 2016 08:58
Last Modified: 08 Dec 2018 06:52
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