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NF-kappaB activation enhances cell death by antimitotic drugs in human prostate cancer cells.
- Source :
-
Molecular cancer [Mol Cancer] 2010 Jul 09; Vol. 9, pp. 182. Date of Electronic Publication: 2010 Jul 09. - Publication Year :
- 2010
-
Abstract
- Background: NF-kappaB is a transcription factor that promotes inhibition of apoptosis and resistance to chemotherapy. It is commonly believed that inhibition of NF-kappaB activity can increase sensitivity of cancer cells to chemotherapy. However, there is evidence that NF-kappaB activation can sensitize cells to apoptosis and that inhibition of NF-kappaB results in resistance to chemotherapy. In prostate cancer, it is not clear in the different cell types (androgen-dependent and castration-resistant) if activation or inhibition of NF-kappaB is required for stimulation of apoptosis by chemotherapy.<br />Results: Our data indicate that the response of prostate cancer (PC) cells to the antimitotic drugs docetaxel (Doc) and 2-methoxyestradiol (2ME2) is dependent on the levels of NF-kappaB activity. In androgen-dependent LNCaP cells, Doc and 2ME2 treatment increased the low basal NF-kappaB activity, as determined by Western blot analysis of phospho-IkappaBalpha/p65, NF-kappaB promoter reporter assays, and p65 localization. Treatment of LNCaP cells with parthenolide, a pharmacologic inhibitor of NF-kappaB, or introduction of dominant-negative IkappaBalpha, or an shRNA specific for p65, a component of the NF-kappaB heterodimer, blocked apoptosis induced by Doc and 2ME2. In castration-resistant DU145 and PC3 cells, Doc and 2ME2 had little effect on the high basal NF-kappaB activity and addition of parthenolide did not enhance cell death. However, the combination of Doc or 2ME2 with betulinic acid (BA), a triterpenoid that activates NF-kappaB, stimulated apoptosis in LNCaP and non-apoptotic cell death in DU145 and PC3 cells. Increased sensitivity to cell death mediated by the Doc or 2ME2 + BA combination is likely due to increased NF-kappaB activity.<br />Conclusions: Our data suggest that the combination of antimitotic drugs with NF-kappaB inhibitors will have antagonistic effects in a common type of PC cell typical of LNCaP. However, combination strategies utilizing antimitotic drugs with BA, an activator of NF-kappaB, will universally enhance cell death in PC cells, notably in the aggressive, castration-resistant variety that does not respond to conventional therapies.
- Subjects :
- 2-Methoxyestradiol
Base Sequence
Blotting, Western
Cell Line, Tumor
DNA Primers
Docetaxel
Estradiol analogs & derivatives
Estradiol pharmacology
Flow Cytometry
Humans
Immunohistochemistry
Male
NF-kappa B antagonists & inhibitors
Pentacyclic Triterpenes
Sesquiterpenes pharmacology
Taxoids pharmacology
Triterpenes pharmacology
Betulinic Acid
Antineoplastic Agents pharmacology
Apoptosis drug effects
Mitosis drug effects
NF-kappa B metabolism
Prostatic Neoplasms pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1476-4598
- Volume :
- 9
- Database :
- MEDLINE
- Journal :
- Molecular cancer
- Publication Type :
- Academic Journal
- Accession number :
- 20618955
- Full Text :
- https://doi.org/10.1186/1476-4598-9-182