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

  1. Author:
    Crea, F.
    Serrat, M. A. D.
    Hurt, E. M.
    Thomas, S. B.
    Danesi, R.
    Farrar, W. L.

  2. Author Address

    [Crea, Francesco; Duhagon Serrat, Maria A.; Hurt, Elaine M.; Farrar, William L.] NCI Frederick, Canc Stem Cell Sect, Lab Canc Prevent, Ctr Canc Res, Frederick, MD 21702 USA. [Crea, Francesco] Scuola Super Sant Anna, Pisa, Italy. [Duhagon Serrat, Maria A.] UDELAR, Lab Interacc Mol, Fac Ciencias, Dept Genet,Fac Med, Montevideo, Uruguay. [Thomas, Suneetha B.] NCI Frederick, Basic Sci Program, SAIC Frederick Inc, Frederick, MD 21702 USA. [Danesi, Romano] Pisa Med Sch, Div Pharmacol, Dept Internal Med, Pisa, Italy.;Farrar, WL, NCI Frederick, Canc Stem Cell Sect, Lab Canc Prevent, Ctr Canc Res, Bldg 560,Room 21-81, Frederick, MD 21702 USA.;farrar@mail.ncifcrf.gov
    1. Year: 2011
    2. Date: Apr
  2. Journal: International Journal of Cancer
    1. 128
    2. 8
    3. Pages: 1946-1954
  4. Type of Article: Article
  5. ISSN: 0020-7136
  1. Abstract:

    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. BMI1controlled 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. Cancer Therapy

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External Sources

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  2. DOI: 10.1002/ijc.25522
  3. View record in Web of Science®
  4. WOS: 000288037400021

Library Notes

  1. Fiscal Year: FY2010-2011
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